InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Biochemistry, Genetics and Molecular Biology » "Free Radicals and Diseases", book edited by Rizwan Ahmad, ISBN 978-953-51-2747-5, Print ISBN 978-953-51-2746-8, Published: October 26, 2016 under CC BY 3.0 license. © The Author(s).

Chapter 14

Free Radicals and Biomarkers Related to the Diagnosis of Cardiorenal Syndrome

By Carolina B.A. Restini, Bruna F.M. Pereira and Tufik M. Geleilete
DOI: 10.5772/63898

Article top

Free Radicals and Biomarkers Related to the Diagnosis of Cardiorenal Syndrome

Carolina B.A. Restini, Bruna F.M. Pereira and Tufik M. Geleilete
Show details


The National Heart, Lung, and Blood Institute Working Group has postulated the cardiorenal syndrome (CRS) as an interaction between the kidneys and the cardiovascular system in which therapy to relieve congestive heart failure (HF) symptoms is limited by the further worsening renal function. CRS is classified from type I to V, taking into account the progression of the symptoms in terms of mechanisms, clinical conditions, and biomarkers. Experimental and clinical studies have shown the kidney as both a trigger and a target to sympathetic nervous system (SNS) overactivity. Renal damage and ischemia, activation of the renin angiotensin aldosterone system (RAAS), and dysfunction of nitric oxide (NO) system are associated with kidney adrenergic activation. Indeed, the imbalances of RAAS and/or SNS share an important common process in CRS: the activation and production of free radicals, especially reactive oxygen species (ROS). The present chapter addresses connections of the free radicals as potential biomarkers as the imbalances in the RAAS and the SNS are developed. Understanding the involvement of free radicals in CRS may bring knowledge to design studies in order to develop accurate pharmacological interventions.

Keywords: Cardiorenal syndrome, renin angiotensin aldosterone system, sympathetic nervous system, reactive oxygem species, free radicals

1. Introduction

Cardiorenal syndrome (CRS) refers to multiple abnormalities characterized by a cluster of concurring symptoms related to cardiac and renal damage. The syndrome is commonly initiated by renal insufficiency secondary to heart failure (HF) [1]. However, the term CRS is also used to describe the negative effects of reduced renal function on the heart and the circulation [2].

A lack of a precise definition to CRS has been pointed out by recognized authors [3]. Based on epidemiologic data, the primary failing organ [4] can be either the heart or the kidney. Therefore, it is accepted that CRS can begin and perpetuate due to a merge in neurohormonal feedback mechanisms involving cardiac and renal dysfunctions. This concept expanded the comprehension about its pathogenesis and treatment.

Ronco et al. and the National Kidney Foundation [5] address CRS as a heart and kidney disorder where acute or chronic dysfunction in one of these organs may induce acute or chronic dysfunction in the other. In addition, Ronco et al. [6] presented a concept that interchanges cardio and renal functions causing CRS and classified it from type I to V, as following:

  • Type I (acute cardiorenal syndrome): acute decline in heart function causing kidney dysfunction.

  • Type II (chronic cardiorenal syndrome): chronic abnormalities in heart function causing kidney dysfunction.

  • Type III (acute renocardiac syndrome): acute decline in kidney function causing heart dysfunction.

  • Type IV (chronic renocardiac syndrome): chronic abnormalities in kidney function causing heart dysfunction.

  • Type V (secondary cardiorenal syndromes): coinciding heart and kidney dysfunction secondary to systemic conditions.

In the next paragraphs each type of CRS will be described, whose injuries are linked to inflammation and to other deleterious processes connected to free radicals generators. Giving its main classification, the key-systems involved in CRS are the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS).

Type I—acute CRS characterized by a rapid worsening of cardiac function that leads to acute kidney injury (AKI). Sudden worsening of cardiac function (due to, e.g., acute cardiogenic shock, acute decompensation of chronic heart failure, procedures like coronary angiography, or cardiac surgery) triggers acute renal dysfunction, which consequently leads to humorally mediated damages that involves the activation of both SNS and RAAS systems, as well as to sodium and water retention, and to vasoconstriction. This process enhances the initial impairment in cardiac function, creating, therefore, a snowball effect.

The acute decline in renal function in CRS type I presents a diagnostic challenge since the activation of inflammatory pathways is involved in the acute impairment and acceleration in cardiovascular pathobiology [4, 7].

Diuretic responsiveness is decreased in CRS type I. In a congestive state, decreased response to diuretics may result from the physiological phenomenon of diuretic braking (diminished diuretic effectiveness secondary to postdiuretic sodium retention) [8].

Type II—chronic CRS. The progressive chronic kidney disease (CKD) is linked to chronic cardiac abnormalities; the main example is congestive heart failure. In fact, reduced renal perfusion is related to the mechanism underlying the long-term aggravation of the renal function in chronic heart failure, which has micro-and macrovascular disease as predisposing factors [9, 10].

Frequently, there can be excessive production of vasoconstrictive mediators (epinephrine, angiotensin, and endothelin) and altered sensitivity and/or release of endogenous vasodilators (natriuretic peptides and nitric oxide—NO) [2].

Among the causes of chronic heart disease that increase susceptibility to kidney impairments toward CKD is low cardiac output, an important cause of chronic kidney hypoperfusion and of apoptosis. Initially, kidney damage begins with the development of sclerosis and fibrosis, related to the low cardiac output, subclinical inflammation, endothelial dysfunction, and accelerated atherosclerosis; these main changes, then, progress to CKD. The most important features of chronic heart disease involved are chronic hypoperfusion, increased renovascular resistance, increased venous pressure, and embolisms.

Regarding the kidney, the main alterations that feed chronic heart disease are anemia, sodium and water retention, calcium and phosphates abnormalities, uremic solute retention, left ventricular hypertrophy, hypertension, and activation of SNS and RAAS.

Type III—acute renocardiac syndrome, which has the abrupt worsening of kidney function as the primary cause (e.g., AKI, ischemia, or glomerulonephritis), being responsible for acute cardiac dysfunction (e.g., heart failure, arrhythmia, and ischemia). Although AKI can affect the heart [6], the cause and effect relationship has not been well established. It is known, nonetheless, that pulmonary edema occurs due to fluid overload, that elevated serum potassium levels could culminate in arrhythmias and cardiac arrest, that uremia builds up myocardial depressant factors affecting negatively the inotropism [11] and could cause inflammatory processes in the pericardium [12], and that high hydrogen ion serum concentration leads to pulmonary vasoconstriction [13], a strong contributor to right-sided heart failure. In addition, low blood pH (acidemia) decreases myocardial contractility [14], and when combined with electrolyte imbalance, heightens the risk of irregular heart rhythms [15]. Ultimately, compromised kidney perfusion alone can initiate inflammatory and apoptotic processes in the heart [3].

Type IV—chronic renocardiac syndrome, in which primary CKD, is the main condition (e.g., chronic glomerular disease) that decreases cardiac function and causes ventricular hypertrophy, diastolic dysfunction, and/or increases the risk of adverse cardiovascular events. According to the National Kidney Foundation [5], CKD is subdivided in five stages based on the severity of kidney damage and glomerular filtration rate.

Type V—secondary CRS characterized by the presence of both cardiac and renal dysfunction is due to acute or chronic systemic disorders. Although systematic information on CRS type V is limited, there is a notorious increase in mortality as more organs fail. Comprehension is limited in terms of how simultaneous renal and cardiovascular failure may affect differently an outcome when compared to simultaneous pulmonary and renal failure, for example. Nonetheless, it is clear that several acute and chronic diseases can affect both organs concurrently and that once started, one organ can affect the other. An example of a very common and serious condition affecting the heart and the kidney is severe sepsis. Other examples include diabetes, amyloidosis, systemic lupus erythematosus, and sarcoidosis. Several chronic conditions such as diabetes and hypertension may contribute to CRS types II and IV.

As seen earlier, an imbalance in the components of the SNS and the RAAS contributes to CRS. Generally, a reduced cardiac output in cardiac heart failure resulting in decreased renal perfusion is thought to be an easy explanation for the worsening renal function [16]. Interestingly though, worsening renal function has been demonstrated in patients with acute decompensated heart failure with preserved left ventricular ejection fraction [17, 18]. This decline in renal function, despite presumed blood flow preservation, has led to an investigation for other mechanisms of CRS, including the role of the renin-angiotensin-aldosterone system (RAAS), of various chemicals (nitric oxide [NO], prostaglandins, natriuretic peptides, endothelins, etc.), of oxidative stress, and of sympathetic overactivity.

The following sections in this chapter aim to conclude that the lack of balance between the RAAS and the SNS triggers deleterious effects in CRS due to processes associated with free radicals production and excessive oxidative stress. Before reaching this conclusion, however, free radical concepts must be addressed.

2. Biomarkers, free radicals, and oxidative stress: basic concepts

A Biomarker is a biological marker that reveals medical signs, in other words, it is an objective indicator of a medical state that can be measured accurately and reproducibly without being invasive [19]. The National Institute of Health Biomarkers Definitions Working Group [20], as well as heads in the field of clinical trials and biostatistics from the US National Institute of Health and the US Food and Drug Administration, developed consistent and comprehensive definitions of terms relating to the use of biomarkers. According to them, a biomarker is objectively measured and evaluated as an indicator of normal biological and pathogenic processes, or pharmacologic responses to a therapeutic intervention. The use of biomarkers in basic and clinical research as well as in clinical practice has become so conventional that it is now accepted almost without question.

A free radical is a molecular species that contains an unpaired electron in an atomic orbital resulting in high reactivity and instability, yet it is capable of independent existence. These molecules can either donate or accept electrons, therefore, behaving as oxidizing or reducing agents [21]. Among the most important free radicals in cardiovascular disease, especially in CRS, are the reactive oxygen species (ROS) composed of: hydroxyl radical (OH•), superoxide anion radical (O•), hydrogen peroxide (H2O2), oxygen singlet (1O2), hypochlorite (ClO), NO radical (NO•), and peroxynitrite radical (ONOO). As other highly reactive species, they are potentially capable of disrupting homeostasis in the nucleus and in the cellular membrane by damaging DNA, proteins, carbohydrates, and lipids [22].

ROS are derived either from normal essential metabolic processes in the human body or from external sources such as exposure to X-rays, ozone, cigarette smoke, air pollutants, and industrial chemicals [23]. Free radical formation occurs continuously in the cells due to enzymatic and nonenzymatic oxygen reactions with organic compounds. Enzymatic reactions that produce free radicals include those involved in the respiratory chain, in phagocytosis, in prostaglandin synthesis, and in the cytochrome P­450 system [24].

The term “oxidative stress” describes the oxidative damage resulting from unfavorable antioxidant defenses against free radical generation [25, 26]. Short-term oxidative stress may occur in tissues injured by trauma, infection, heat, hypertonia, toxins, or excessive exercise. Injured tissues produce higher levels of radical generating enzymes (e.g., xanthine oxidase, lipogenase, and cyclooxygenase), increase phagocyte activation and free iron and copper release, and produce an excess of ROS by disrupting the electron transport and oxidative phosphorylation. The initial mutation and progression of cancer, as well as the side effects of radiation and chemotherapy, have all been linked to the imbalance between ROS and the antioxidant defense system.

In addition, ROS has been implicated in the induction and in the complications of cardiac and renal [27] dysfunctions related to CRS [28] through the SNS and the RAAS [29].

3. RAAS and SNS: renal and cardiovascular systems

This section attempts to explain basic concepts about the signaling transductions of the RAAS and the SNS involved in CRS progression.

The RAAS plays an important role in systemic blood pressure regulation as well as in fluid and in electrolyte balance [30]. Angiotensin II (Ang II), the main effector peptide, is involved in cardiovascular and renal physiological and pathological effects, with inflammatory aspects [31] of different diseases present in CRS.

3.1. Ang II and its main signaling pathways to produce cardio and renal injuries

AT1 and AT2 are the main receptors activated by Ang II, being the first prominent receptor involved in harmful consequences of RAAS activation.

The main effect of Ang II is vasoconstriction by [3234] increasing sympathetic tone [35] and arginine vasopressin (AVP) release [3638] through stimulation of AT1 receptors mainly present in the vasculature. Activation of Ang II receptors and even nonreceptor pathways has been presented in a review by Touyz and Berry [39]. Briefly, ligand-receptor binding leads to activation of G proteins through an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP), releasing α and β-γ complexes, which mediate downstream actions. AT1 receptors can be interacted with various heterotrimeric G proteins including Gq/11, Gi, Gα12, and Gα13. Different G protein isoforms lead to distinct signaling cascades. Gq activation results in the activation of phospholipase C (PLC), whereas GαI leads to cGMP formation. Although G protein-coupled receptors do not contain intrinsic kinase activity, the members of the G protein receptor kinase family phosphorylate the G protein-coupled receptors on serine and threonine residues. AT1 receptors are phosphorylated in response to Ang II stimulation. Several tyrosine kinases, including Janus kinases (JAK and TYK), Src family kinases, and focal adhesion kinase (FAK) can phosphorylate AT1 receptors [40].

Angiotensin II has a long-term control over blood pressure through various mechanisms: direct stimulation of AT1 kidney receptors [10] and indirect adrenal gland aldosterone releasing regulate renal reabsorption of sodium and water [41], and acts on the hypothalamus causing thirst [36, 37].

The renin activity on the α2-globulin angiotensinogen produces the decapeptide angiotensin I (Ang I), which is then cleaved by an angiotensin-converting enzyme (ACE) to produce the octapeptide Ang II [42].

In mammals, there are two isoforms of ACE: somatic ACE, abundant on the surface of pulmonary endothelial cells, and testicular ACE. Both isoforms are found as soluble enzymes in the plasma and in seminal fluid [43]. Production of Ang II from Ang I also occurs through an ACE-independent way by the activity of other enzymes such as cathepsin G, a chymostatin-sensitive Ang II-generating enzyme, and chymase [36].

Besides its primary vasoconstrictor effects, Ang II also presents growth factor and cytokine-like properties [44]. The different forms of intracellular signaling processes explain its varied effects. In VSMC and also in renal cells, including glomerular endothelial and mesangial cells, Ang II induces chemokines such as monocyte chemoattractant protein-1 (MCP-1) [4548].

AT1 signaling through phospholipids involves phospholipase C (PLC), phospholipase D (PLD), and phospholipase A2 (PLA2).

PLC signaling results in rapid production of the second messengers 1,4,5-inositol triphosphate (IP3) and diacylglycerol (DAG). While IP3 stimulates Ca2+ mobilization from the sarcoplasmic reticulum, DAG causes Ca2+ influx from extracellular space after protein kinase C (PKC) stimulation [49]. The increased cytoplasmic calcium concentration ([Ca2+] c) leads to Ca2+-dependent, calmodulin-activated phosphorylation of the myosin light chain, which, in turn, leads to cellular contraction. This is the main mechanism involved in the vascular smooth muscle cell (VSMC) contraction. PKC activation by this process regulates intracellular pH through the Na+/H+ exchanger [49, 50] and also activates both the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) signaling as well as the ROS production.

PLD signaling is related to the phosphatidylcholine hydrolysis. The AT1 receptors mediating PLD activation involve Gβ-γ, Gα12, Src, and RhoA [51]. The pathways associated with Ang II-induced activation of PLD in VSMC are PKC independent, but involve intracellular Ca2+ mobilization and Ca2+ influx that is tyrosine kinase-dependent. Ang II-induced PLD signaling has been implicated in cardiac hypertrophy, VSMC proliferation, and vascular contractility [52, 53]. Among the PLD-mediated responses, there are vascular generation of superoxide anions by stimulating NADPH oxidase, and, under long-term stimulation of AT1 receptors, growth and remodeling in the cardiovascular system [54].

The PLA2 activation due to Ang II binding on AT1 receptors is responsible for arachidonic acid release from cell membrane phospholipids [55], and its consequent metabolism by cyclooxygenases, lipoxygenases, or cytochrome P450 oxygenases results in various different eicosanoids influencing vascular and renal mechanisms that are important in blood pressure regulation. The main PLA2-derived eicosanoids resultants from cyclooxygenases include prostaglandin (PG) H2, which is then converted to thromboxane (Tx), PGI2 (prostacyclin), or to PGE2, PGD2, or PGF2α, by different enzymes (22). Lipoxygenases-derived molecules are the leukotrienes [55]. Cytochrome P450 oxygenases leads to the production of the hydroxy-eicosatetraenoic acids (HETE)—acids derived from epoxidation and allylic oxidation.

In VSMC, AT1 receptor stimulation by Ang II interconnects all phospholipases (PLA2, PLD, and PKC) activation to initiate NADPH oxidase activity. DAG and Ca2+, from the sarcoplasmic reticulum by IP3, activate PKC, which leads to phosphorylation of p47phox and initial activation of the NADPH oxidase [56, 57]. PLD also mediates PKC activation; phosphatic acid (PA) is produced, serving as a source of DAG [5860]. Furthermore, PLA2 is activated by calcium cleaving phosphatidylcholine to products that heightens NADPH oxidase action, lysophosphatidylcholine (LPC) and arachidonic acid (AA) [61].

AT1-mediated tyrosine phosphorylation leads to mitogen-activated protein kinase (MAPK) activation associated with growth factors and cytokine activity, which corroborate to mitogenic and inflammatory consequences of Ang II. Moreover, AT1 receptor activation may be mediated by the activation of receptor tyrosine kinases (RTK) to bring about the Ang II stimuli on epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and insulin growth factor receptor (IGFR) [62, 63].

Furthermore, Ang II stimulates phosphorylation of several nonreceptor tyrosine kinases such as PLC-γ, Src family kinases, Janus kinase (JAK), focal adhesion kinase (FAK), Ca2+-dependent tyrosine kinases, p130Cas, and phosphatidylinositol 3-kinase (PI3K) [64]. Altered VSMC function in hypertension is associated with increased activation of c-Src by Ang II. Vascular and cardiac growth, remodeling, and repair are assumed to involve Janus kinase, and the signal transducers and activators of transcription from early growth response genes mediated by Ang II [65]. FAK-dependent signaling pathways triggered by Ang II are related to cell migration and changes in cell shape and volume [66]. p130Cas mediated-Ang II effects regulate α-actin expression, cellular proliferation and migration, and cell adhesion, playing a relevant role in cardiovascular disease and actin filament assembly [67]. PI3K in Ang II signaling in VSMC may control the balance between mitogenesis and apoptosis [68].

Ang II activates the three major members of the mitogen-activated protein kinases (MAPK) family [69, 70]: ERK1/2 (related to enhanced proto-oncogene expression, and activation of the transcription factor, cell cycle progression, and protein synthesis in VSMC [71]), JNKs (regulation of cell growth, and vascular damage associated with cardiovascular disease [72]), and p38 MAPK (inflammatory responses, apoptosis, and inhibition of cell growth [73]).

Finally, by signaling through heterotrimeric G proteins, AT1 receptors activate monomeric small (21 kDa) guanine nucleotide-binding proteins (small G proteins) in VSMC. Activation of Ang II via AT1 receptor is coupled with Rho subfamily (RhoA, Rac1, and Cdc42), whose Ang II effects are associated with increased Ca2+ sensitization, VSMC contraction, cytoskeletal organization, cell growth, inflammation, and regulation of NADPH oxidase [74]. In general Ang II, as other Gq coupled receptors, effectively activates NADPH oxidase in the cardiovascular system, enhancing production of ROS, whose effects majorly contribute to the pathogenesis of cardiovascular and kidney disease [75].

The integration of all the concepts above leads to the comprehension that important deleterious effects of Ang II could contribute to features observed in the CRS. This is supported by therapeutic involvement of angiotensin-converting enzyme inhibitors (ACEi) and of angiotensin receptor inhibitor, which have proven to be effective in the CRS therapy (for pharmacotherapy guidance we suggest reading the guideline organized by Dickstein et al. [76]). The activation of the RAAS determines renal hypoxia, vasoconstriction, intraglomerular hypertension, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria [77]. Similarly, the activation of the SNS involves proliferation of smooth muscle cells and adventitial fibroblasts in the intrarenal vascular walls [78]. Ang II increases renal vascular resistance in animal models, and the addition of an α2-adrenoceptors agonist enhances this response. NADPH oxidase inhibition, as well as Rho kinase inhibition, or the presence of a superoxide dismutase (SOD) mimetic attenuates this interaction between Ang II and α2-adrenoceptors agonist. Furthermore, in preglomerular VSMCs, the α2-adrenoceptors agonist enhanced Ang II-induced intracellular O2- production and activation of RhoA, responses which were prevented by inhibition of phospholipase C (PLC), PKC, c-Src, NADPH oxidase, and by a SOD mimetic.

3.2. Free radicals: key biomarkers in experimental models to explain RAAS and SNS in CRS

Excessive and inappropriate activation of the RAAS [79] is directly implicated in many ways in the progression of renal disease due to heart failure. In parallel to the heart failure, the ongoing, uncontrolled activation of the RAAS is indicative of renal failure.

The model proposed by Guyton [80] describes a heart–kidney connection regarding extracellular fluid volume (ECFV), cardiac output, and mean arterial pressure. In this arrangement, the pathophysiological basis of CRS is structured on the combined renal and cardiac disease invoking a number of specific factors that synergistically aggravate the disease.

In Guyton’s model [80], the kidney is placed as a regulator of extracellular fluid volume and the RAAS is placed with its corresponding extensions (aldosterone and endothelin) and its antagonists (natriuretic peptides and NO). The model explains changes in extracellular fluid volume, blood pressure, and cardiac output in merged heart and renal failure. An extension to this model, however, was projected by Bongartz et al. [29] to explain the accelerated atherosclerosis, the cardiac remodeling and hypertrophy, and the progression of renal disease observed in the severe CRS. When the heart or the kidney fails, a vicious cycle, called the cardio-renal connection [81, 82] in a scheme depicted by Bongartz et al. [29], progresses: the RAAS, the NO-ROS balance, the sympathetic nervous system, and inflammation interact and synergize.

The reduction in circulating arterial blood volume triggers arterial baroreceptors and activates neurohormonal pathways resulting in compensatory mechanisms in order to restore physiological tissue perfusion to correct the relative hypovolemia, such as in hemorrhage [83].

Indeed, not only the RAAS is activated but also the SNS. The endothelin and arginine-vasopressin systems are triggered by low renal function as protection mechanisms. Additionally, sodium-retentive vasoconstriction can counterbalance the activation of vasodilatory natriuretic hormone (natriuretic peptide) systems and cytokines (prostaglandins, bradykinin, and NO) [84].

These pathways lead to an outcome of heart failure, an impairment involving volume retention due to hemodynamics and reabsorptive actions of angiotensin II (Ang II) [86].

In addition to the imbalance of extracellular fluid volume (ECFV) and vasoconstriction, the activation of NADPH-oxidase by Ang II harms the cardiorenal connection by generating ROS [87].

Ang II not only stimulates NADPH oxidase-dependent O2 production in VSMCs but also in endothelial cells and adventitial fibroblasts [88, 89]. Additionally, stretch of the vasculature could enhance O2 and hydrogen peroxide (H2O2) production by NADPH oxidase during a relatively short period of time [90, 91].

Mohazzab and Wolin [92] and Rajagopalan et al. [93] have identified NADPH oxidase as a major site of O2 generation in intact arteries (endothelial cells and vascular smooth muscle cells [94]) besides renal tubular cells [95] and cardiomyocytes [96]. Interestingly, constituents of phagocyte NADPH oxidase were found in many different tissues, like in mesangial cells [97], vascular smooth muscle cells [98, 99], endothelial cells [100], glomerular epithelial podocytes [101], kidney proximal tubular epithelial cells [102], and fibroblasts [103].

The multimolecular enzyme NADPH oxidase has the following components: a membrane-associated 22-kDa α-subunit (p22phox) and a 91-kDa β-subunit (gp91phox) with cytoplasmic constituents (p47phox, p67phox, and p40phox) [104].

The severity of CRS is positively associated with oxidative damage to renal tubular or interstitial cells due to interference with feedback systems involved in renin secretion and angiotensin formation. Chronic inhibition of NO synthesis causes upregulation of cardiac ACE and Ang II receptors, possibly mediating inflammatory changes [105]. It has been demonstrated [105] a complete NADPH oxidase system along the luminal membrane of the macula densa, suggesting that O2- generated at this site forms a barrier and limits the actions of NO locally generated to reach targets on the luminal membrane. Thus, local NADPH oxidase impairs the bioavailability of NO, which is implicated by the regulation of sodium reabsorption in distal nephrons and activation of macula densa cells of hypertensive rats.

Renal blood flow reduction due to activation of the RAS leads to stimulation of the macula densa and subsequent secretion of renin; in critical kidney impairment (such as in hypoxia), this vicious cycle of RAAS starts or maintains the development of CRS [27].

Ang II may produce cell changes in the glomerular epithelium [106]. Local expression of the RAS in podocytes has been recently confirmed in human podocytes [107, 108]. Direct injury to podocytes of transgenic rat models with overexpression of the human Ang II Type 1 receptor, developed substantial selective proteinuria (albuminuria) without an increase in blood pressure. This model’s glomerular injury led to nephron loss through the classic pathway present in focal segmental glomerulosclerosis [109]. Also, aldosterone, an end product of Ang II, directly injures podocytes [110, 111].

Therefore, added to these direct consequences of tubulointerstitial damages, present mainly in CRS type II, activation of this system can induce glomerulosclerosis and anatomical damage to glomerular tufts, with a subsequent decrease in postglomerular capillary perfusion.

Beswick et al. [112] identified ROS production in a model of mineralocorticoid (deoxycorticosterone acetate [DOCA]-salt) hypertensive rats. NADPH oxidase activity is increased in the aortic wall of the DOCA-salt rat, and such an increase is associated with elevated O2 production; long-term inhibition of NADPH oxidase significantly decreased O2 production and systolic blood pressure, but treatment of DOCA-salt rats with the losartan (Ang II inhibitor) does not significantly alter blood pressure, suggesting that locally produced Ang II does not contribute to the elevated peripheral vascular resistance. This calls into question the role of Ang II in O2 generation in this model. On the other hand, NADPH-oxidase mediated ROS release in glomeruli of Dahl [113] salt-sensitive rats with heart failure, which was attenuated by ACEi [114]. In human beings, similarly, NADPH-oxidase is active in the hearts of patients with end-stage heart failure [115]. Inhibition of ACE possibly decreases vascular oxidative stress and/or improves extracellular SOD activity in patients with coronary artery disease due to higher NO bioavailability [116].

Ang II has a role in vascular inflammation via the nuclear factor kappa B (NF-kB) pathway, responsible for producing chemotactic and adhesion molecules [117, 118].

Complicated mechanisms link the RAS to the SNS [119]. The rise of sympathetic hyperactivity detected in kidney failure has been attributed to the failing organ [120], and ACEi could control this outflow in chronic failure [121, 122]. Blocking Ang II signaling transduction causes reduced SNS hyperactivity after myocardial infarction in rats, attenuating ensuing development of heart failure [123].

Oxidative stress induced by hydrogen peroxide presented higher activation of preganglionic sympathetic neurons both in vivo and in vitro in rats, culminating in a greater mean blood pressure and pulse [124]. Moreover, spontaneously hypertensive rats were found to have sympathetic renal activity controlled by vascular superoxide concentrations [125].

4. Oxidative stress in target CRS organs

Considering the RAAS and the SNS and that the impaired functions of the target organs (kidney and heart) can conjointly trigger and intensify diseases related to the syndrome’s development, this section aims to provide the reader with molecular/cellular explanations about why free radicals and consequent oxidative stress are feasible to act as CRS biomarkers.

4.1. Heart and oxidative stress

ATP is constantly demanded in physiologic cardiac functioning. So mitochondria organelles, as major sources of ATP, must be in prompt activity to keep homeostasis [126]. When the balance between cardiac cells and mitochondria is lost, there is cardiac damage due to increased oxidative stress as can be observed in heart failure.

In a normal heart, most of the ATP is produced by fatty acid oxidation, while the remaining part is due to oxidizing pyruvate, an end product of glycolysis or derived from lactate [127]. On the other hand, with decreasing ATP concentrations, there is a metabolic shift from fatty acid oxidation to glycolysis in cardiomyocytes under heart failure progression [128130]. Indeed, the decrease in mitochondrial oxidative metabolism is reduced by a compensatory increase in glucose uptake and glycolysis [131, 132].

The main cause of the damage affecting the cardiomyocytes is the self-perpetuation of the oxidative stress as the reduced oxidative metabolism leads to an accumulation of free fatty acid in cardiomyocytes.

The PKC activation and consequent sarcoplasmic reticulum stress are the main intracellular mechanisms explaining both contributors to mitochondrial oxidative stress: lipotoxicity of circulating fatty acid and intracellular lipid accumulation [133].

Independent of the heart failure stage, changes in mitochondrial electron transport chain components were described [134137]. Indeed, the progressive decrease of ATP production is linked to both a decrease of fatty acid oxidation and a reduction of mitochondrial respiration due to electron transport chain defects [138].

The disruption of the mitochondrial electron transport chain homeostasis is a well-established source of ROS that forms a vicious cycle by amplifying the electron transport chain dysfunctions. In heart failure, the decreased mitochondrial respiratory activity leads to a further drop in oxidative phosphorylation, associated with an increased electron leakage and superoxide generation.

As already mentioned, ROS are produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX). There are seven NOX isoforms that function primarily as ROS-generating enzymes, being important sources of O2 and H2O2 in the cardiovascular system [139]. When physiological functioning of NOXs is disrupted, the production of ROS increases.

Overactivation of the RAAS and the SNS are essential to maintain and amplify the oxidative stress in heart failure, as previously explained. NADPH oxidase activated by Ang II is the primary source of ROS that produces mitochondrial dysfunction [140]. The effects are due to both NOX4 and NOX2, which are upregulated by Ang II in a mitochondrial ROS-independent and dependent manner, respectively [141].

ROS accounts for the damage observed in heart failure, such as cardiac remodeling, cardiomyocyte contractility, ion transport, and Ca2+ handling. ROS act on multiple intracellular signaling pathways for transcriptional activation of selected nuclear genes and finally eliciting transcriptional reprogramming [142]. In response, the most prominent adaptive processes accompanying HF are an increase in sympathetic tone. Increased adrenergic activity causes a reduction on the physiological role of respirasomes, and consequently mitochondrial dysfunction, and a gradual decrease in the cardiac performance [28]. The excessive sympathetic activity can induce cardiomyocyte apoptosis, hypertrophy, and focal myocardial necrosis [85].

The lack of energy in cardiomyocytes is an important result of the oxidative stress observed in decompensated HF, explained by reduced Ca2+ sensitivity in response to oxidative impairment of myofibrillar proteins [143].

ROS were shown to activate matrix metalloproteinase (MMP) in cardiac fibroblasts [144]. MMP are a large family of Ca2+-dependent zinc-containing endopeptidases that are responsible for tissue remodeling and degradation of extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. Overexpression of MMPs results in imbalance between its activity and the activity of TIMPs and can lead to a variety of disorders [145149]. Since MMP plays a central role in organ development and subsequent tissue remodeling in inflammation and in injury, they are relevant HF biomarkers, especially in CRS [150].

4.2. Kidney and oxidative stress

Oxidative stress and inflammation are progressively enhanced in progressing stages of kidney diseases directly related to CRS such as CKD [151153]. This section describes mechanisms that link RAAS and its components to the increased oxidative stress and inflammation within the kidneys [154156].

Ang II acts preferentially in tubular epithelial cells, whereas aldosterone acts in podocyte injury [157]. As previously said, NOX enzymes (NADPH oxidases) are the primary source of ROS. Under Ang II and aldosterone stimuli, cytosolic subunits of NADPH oxidase can translocate into the mitochondrial membrane and increase ROS production and affect the NO function. It is the balance between NO and Ang II rather than their absolute concentration that determines the physiological/pathophysiological effects on multiple organ systems including cardiovascular and renal systems. Ang II systematically decreases regional blood flows, impairs renal function, and causes cardiac hypertrophy [158].

In the kidney, NOX are active in vascular smooth cells in both cortex and medulla [159, 160]. NOX4, NOX2, and NOX1 are expressed in the kidney cortex, being NOX4 the most abundantly expressed renal isoform, primarily not only located in renal tubular cell [161163] but also found in glomerular mesangial cells [164, 165].

A critical role played by NOX-produced ROS is the uncoupling of NO synthase (NOS). Considering its physiological role, NO produced by endothelial cells causes vasodilatation of the afferent arteriole, consequently increasing renal blood flow, attenuating tubuloglomerular feedback, and promoting pressure natriuresis [166]. NO stimulates soluble guanylyl cyclase (sGC) and increases cGMP production that triggers cGMP-dependent protein kinases, phosphodiesterases, and ion channels [167]. On the other hand, NO is activated in a non-cGMP-dependent process and causes covalent proteins changes [168]. NO reacts with O2 to form ONOO [169], therefore, limiting its physiological activity of afferent arteriole relaxation [170, 171], which leads to reduced renal blood flow. Vasoconstriction, inflammation, and impaired vascular and renal functions [172] are the main results of ONOO accumulation.

O2 and ONOO are the main free radicals that start proinflammatory and profibrotic cascades [55]. In the absence of or in a low concentration of NO, the cyclooxygenases (COX) activity is amplified, so vasoconstriction is enhanced due to TxA2, yet the vascular relaxation is impaired due to reduced PGI2 production [172, 173].

Mesangial cell apoptosis [174] and cellular hypertrophy, respectively, due to MAP kinase and ERK1/ERK2 pathways [175], explain the development of epithelial-mesenchymal transition (EMT) [176, 177] caused by NOX-derived ROS. EMT of tubular epithelial cells is characterized by loss of epithelial properties and gain of excessive deposition of extracellular matrix-producing characteristics of myofibroblast [178, 179]. The transforming growth factor β (TGF-β) induces EMT and is assumed to be one of the major causes of renal fibrosis [180182].

According to Yang and Liu [183], and to Rubattu et al. [28], EMT regulates the loss of epithelial cell adhesion, the de novo α-smooth muscle actin (α-SMA) expression and reorganization, the disruption of tubular basement membrane, and the enhanced cell migration and invasion into the interstitium. Increased expressions of PLA2, MCP-1, CSF-1, and COX-2 promote fibrosis and inflammation on renal interstitium, all due to NOX activation under oxidative stress progression [184187]. The main transcription factors involved are NF-kB [74] and c-jun [188].

Second, free radicals’ inflammatory effects can be related to uncoupling proteins (UCPs) [189, 190]. UCPs are mitochondrial transporters present in the inner membrane; they belong to the family of anion mitochondrial carriers including adenine nucleotide transporters. There are three UCPs (1–3). In comparison to the established uncoupling and thermogenic activities of UCP1, UCP2, and UCP3 appear to be involved in the limitation of free radical levels in cells rather than in physiological uncoupling and thermogenesis.

UCP2 gene variants are positively associated with kidney diseases, being considered as a predictor of genetic risk for CKD [191, 192].

5. Oxidative stress: biomarkers and therapeutic strategies in CRS

The main proposal of biomarkers is an early diagnosis of CRS allowing early therapeutic intervention. The continuance of mitochondrial biogenesis against cardiac insult and the reduction of mitochondrial ROS production are the two most promising approaches that may soon yield effective treatments for HF [193].

The action of ROS and their products in organs, such as heart, kidney, and the entire cardiovascular system, turn them into promising biomarkers for predicting cardiovascular risk in CRS and also for therapeutic responses. Important investigations have characterized new oxidation byproducts in specific circumstances, however, oxidized lipoproteins, including low-density lipoproteins (LDL) have a long track record as biomarkers and appear to be among the most promising oxidation markers to potentially impact clinical practice in the near future [194]. Nonetheless, this biomarker is more appropriate for atherosclerosis than for HF related to CRS. Biomarkers such as MMP and mitochondrial function may be more adequate.

Concerning clinical evaluation of cardiovascular and renal dysfunctions, ROS is examined due to the association between plasma and urine markers of oxidative stress. There are several clinical studies where biomarkers were and are being tested [195]. The following sections attempt to cover potential biomarkers related to oxidative stress.

5.1. Heart biomarkers of oxidative stress

The main molecules approached in this section are the ones involved in HF since this is the main cardiac disease in CRS linked to kidney dysfunction.

The molecules are matrix metalloproteinase (MMP), myeloperoxidases (MPO), and mid-regional proadrenomedullin (MR-proADM).

Although HF, but not myocardial infarction, is the main cardiac disease related to CRS, studies have shown that increased MMP production is a biomarker related to both. Since dramatic reduction in the incidence of rupture and reduction in heart size and development of heart failure is observed when MMP activation is reduced, it can predict CKD present in CRS [196].

Considering the role of MMP in stem cell mobilization following cardiac injury, in the very active field of cell-based therapy following myocardial infarction, MMP-9 was found in bone marrow; its function is to release mononuclear cells into the blood flow. After ischemic injury, there seems there to be local formation of inflammatory cytokines, such as tumor necrosis factor (TNF), platelet-derived growth factor, and vascular endothelial growth factor [197]. A significant component of regulation of MMP production following myocardial infarction is induced by the local inflammatory cytokines, which is practically what is observed in HF. Excess TNF in the myocardium has direct relation to an elevated formation of local MMP-9 and MMP-2, and this is associated with modifications in integrin isoform transition [196]. The consequence is aggressive collagen dissolution with possible acute myocardial rupture. If the dissolution goes on without rupture, the heart becomes expressively dilated, with decreased function and poor survival [196]. On the other hand, if the gene for TNF is removed, there is a significant reduction in the levels of the inflammatory cytokines associated with the reduction in MMP activation.

Once MMP are formed, they stay as proenzymes in the ground substance of the extracellular space. However, if met by other activation signals like oxygen free radicals and ischemic triggers such as thrombin or chymase or angiotensin-converting enzyme (ACE) from mast cells, then propeptides are unconfined, liberating the enzyme’s active site [198]. A membrane type MMP can also catalyze this process or other proteolytic agents such as plasminogen activators (urokinase-type plasminogen activator) or plasmin. Plasmin’s activation is due to inflammation and coagulation cascades. Reduction in cardiac rupture after myocardial infarction could be reached by inhibiting MMPs, plasminogen activators, or cytokines [196, 198].

Taking into account the kidney and the heart to explain the role of the free radicals, Rubattu et al. [28] published a review about pathogenesis of CRS and oxidative stress. The information is addressed briefly in the next paragraphs. Myocardial MMP activity is also increased in the failing heart [199]. Sustained MMP activation causes structural changes due to an abnormal extracellular environment for myocytes. Dimethylthiourea, a hydroxyl radical scavenger, inhibits matrix metalloproteinase 2 (MMP2) activation parallel to left ventricular remodeling and failure [200]. Additionally, release of mitochondrial intermembrane proteins crucially triggers apoptotic pathways: cytochrome c, endonuclease G (EndoG), apoptosis-inducing factor (AIF), and second mitochondria-derived activator of caspase (Smac) lead to caspase activation, nuclear DNA fragmentation, and cell death [201]. Release and nuclear translocation of EndoG and AIF stimulate DNA degeneration, independent of caspase activation [202]. Stress kinases, such as c-Jun N-terminal kinase (JNK) and p38-mitogen activated protein kinase (MAPK), are activated by increase in ROS levels [203]. The link between hypertrophy mitochondrial dysfunction seen in HF could be due to JNK. Actually, in addition to the induction of hypertrophic cardiomyocytes, JNK promotes autophagy through Bcl-2 and 19-KDa interacting protein-3 (BNIP3), eventually leading to mitophagy [204, 205]. In turn, higher mitophagy rates ends in MMP activation [206].

Besides the MMP, there are the myeloperoxidases (MPO) considered a key player in the initiation and maintenance of chronic heart failure (CHF) by contributing to intracellular NO depletion. NO consumption through MPO activity may lead to protein chlorination or nitration and to tissue damage.

As revised by Anatoliotakis et al. [207], the principal mechanism by which MPO exerts its effects on the human heart and vessels is thought to be by direct effects of oxidative products on the arterial wall causing endothelial dysfunction, as well as by affecting the function and distribution of cholesterol in the form of LDL and HDL. MPO is the main molecule responsible for lipid peroxidation and conversion of LDL to an atherogenic form that is subsequently taken up by macrophages, a step crucial for the formation of foam cells [208]. Additionally, MPO acts as an enzymatic sink for NO, thus impairing NO-dependent blood vessel relaxation and guanylate cyclase activation [209].

La Rocca et al. [210] demonstrated that human endocardial endothelial cells can express MPO after oxidative stress through the buildup of the end product, 3-chlorotyrosine. Abnormalities in endothelial functions may lead to many cardiovascular issues, including CHF. The authors concluded that the endothelium suffers the consequences as well as plays an important role in cardiovascular stress due to oxidation.

Considering what was the earlier approach about CRS, a positive association can be made with an MPO increase and disease progression. MPO, a marker of oxidative stress [211, 212], maintained a modest association with HF in this cohort when combined with each of the established and emerging biomarkers.

MR-proADM shows great promise as an independent prognostic tool for cardiac diseases. Although it has been shown as a strong predictive marker for a variety of cardiac disease, it is also a biomarker for other diseases including chronic obstructive pulmonary disorder, pneumonia, and pulmonary embolism [213, 214]. Since MR-proADM levels have been shown to differ based on New York Heart Association (NYHA) class and severity of HF, it has the potential to help identify those patients who may benefit from more invasive therapy [215].

Adrenomedullin (ADM), a 52-amino-acid peptide, was first discovered from a pheochromocytoma. It is expressed by many endothelial tissues throughout the body including the adrenal medulla, lungs, kidneys, gastrointestinal organs, and heart [216219]. ADM is secreted as an inactive precursor (pro-ADM) and subsequently cleaved into the active form where it acts as a potent vasodilator through the nitric oxide pathway and increases diuresis and natriuresis [220222].

Considering emerging biomarkers of hemodynamic stress that are strongly predictive of poor outcomes in patients with heart failure (HF), MR-proADM is the main molecule related to CRS [223]; others include copeptin and midregional proatrial natriuretic peptide [MR-proANP].

5.2. Kidney biomarkers of oxidative stress

Considering renal biomarkers of oxidative stress as part of the pathophysiology, the pool includes oxidized low-density lipoproteins (Ox-LDL), advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS), plasma and urinary F2-isoprostanes, malondialdehyde (MDA), protein reduced thiols, total antioxidant status (TAS), protein carbonyls, advanced glycation end products (AGE), rinary 8-hydroxydeoxy guanosine (8-OHdG), 4-hydroxy-nonenal, antioxidant enzyme activities (e.g., superoxide dismutase, glutathione peroxidase, and catalase) [195, 224229]. It is important to highlight that these biomarkers could indicate the possible correlated diseases, and not strictly renal injuries from CRS. Studies that involve cardiovascular and kidney disease, such as hypertension and CRS, try to correlate oxidative stress to the absence of antioxidant defenses (extrinsic and intrinsic). In general oxidized phospholipids (OxPL) have been associated with cardiovascular disease and new cardiovascular events [230]. OX-LDL, a particle derived from circulating LDL, may have peroxides or their degradation products generated within the LDL molecule or elsewhere in the body. This includes minimally oxidized LDL, but not apoprotein changes, and malondialdehyde (MDA) modified particles with MDA arising from platelets or elsewhere. However, LDL particles with oxidized apo B amino acids without lipid changes have not been described [231]. In kidney diseases, Ox-LDL has been studied as a biomarker to assess end-stage renal failure. Nonetheless, as a CRS biomarker, Ox-LDL needs correlational studies [232].

According to Witko-Sarsat et al. [233], AOPP is a biomarker of phagocyte-derived oxidative stress. The authors point out the role of AOPP in the pathophysiology of chronic renal failure and dialysis-related complications. Considering AOPP production, they describe that myeloperoxidase (MPO) has a significant role in the consequent formation of chlorinated oxidants, contrary to the prior belief of its sole microbicidal action. Undeniably, AOPP seems to mediate inflammation because they can initiate the oxidative burst and the production of cytokines in leucocytes. Therefore, it can be inferred that by the uremia-associated defect in anti-oxidant systems that the AOPP, from the reaction between chlorinated oxidants and plasma proteins, constitute new uremic toxins with proinflammatory effects. Specific plasma proteins are critical targets for oxidants that can be evaluated by spectrophotometric assays, which allows AOPP detection in uremic plasma [234], mainly from patients under hemodialysis [235].

F2-isoprostanes are a series of active compounds like prostaglandin F2. They are produced regardless of the route of the COX in the peroxidation of AA. F2-isoprostanes are formed in situ on the membrane phospholipid chains and subsequently released. Their concentrations in the plasma and urine of healthy adults are 10–100 times greater than those of prostanoid formed by way of the cyclooxygenase. They significantly increase oxidative stress. The F2 isoprostanes are potential markers of lipid peroxidation, but their measurement requires sophisticated equipment (mass spectrometer). Recently, Elisa methods have become available [236].

Biomarkers of cell damage due to systemic oxidative stress, such as plasma thiobarbituric acid-reactive substances (TBARS) and 8-epi-isoprostanes, are elevated in patients with hypertension [237, 238] who mainly present kidney injury. Antioxidant capacity and the levels of antioxidant vitamins and enzymes were reduced in patients with hypertension [239, 240] with renal insufficiency.

6. Conclusion

The Acute Decompensated Heart Failure National Registry (ADHERE) database has pointed out that renal dysfunction in patients with heart failure is complex and often multifactorial in origin. Along these lines, CRS is conceived as a moderate or a greater renal dysfunction existing or developing in a patient with decompensated heart failure during treatment [241]. Important works present a common agreement: concurrent kidney and heart failure has a bad prognosis [242244]. The literature, on the other hand, is not homogeneous in relation to the damages and their mechanisms due to a number of factors, causes, and on the processes that makes CRS reversable in some cases. Since both the RAAS and the SNS are related to the processes leading to inflammation and are tightly involved in production and/or activation of free radicals, this chapter’s rationale is that the diagnosis and progression of CRS could be evaluated through oxidative stress. Some CRS pharmacotherapeutics approaches are deficient, although mainly involving the primary condition linking renal dysfunction to heart failure, like in volume-loaded patients with diuretic braking [245]. There is a gap in clinical trials composed of patients with heart failure and with substantial kidney dysfunction, because most patients are recruited from a population with relatively preserved kidney function [246]. Further studies are needed to better define renal function in patients with heart failure or vice-versa. Attention must be taken to drugs that may impair kidney function, and specially evaluated regarding populations selected for clinical trials, who have already had their kidney functions compromised or put at risk. Understanding the involvement of free radicals in the Cardiorenal Syndrome could lead to accurate pharmacological studies and future interventions.


1 - Liang KV, Williams AW, Greene EL, Redfield MM. Acute decompensated heart failure and the cardiorenal syndrome. Crit Care Med. 2008;36:S75–S88. DOI: 10.1097/01.CCM.0000296270.41256.5C.
2 - Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med. 2008;34:957–962. DOi: 10.1016/j.jacc.2008.07.051.
3 - Patel J, Heywood JT. Management of the cardiorenal syndrome in heart failure. Curr Cardiol Rep. 2006;8:211–216. DOI: 10.1007/s11886-006-0036-8.
4 - Berl T, Henrich W. Kidney-heart interactions: epidemiology, patho-genesis, and treatment. Clin J Am Soc Nephrol. 2006;1:8–18. DOI: 10.2215/CJN.00730805.
5 - National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–S266. DOI: 10.7326/0003-4819-139-2-200307150-00013.
6 - Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–1539. DOI: 10.1016/j.jacc.2008.07.051.
7 - Tokuyama H, Kelly DJ, Zhang Y, Gow RM, Gilbert RE. Macrophage infiltration and cellular proliferation in the non-ischemic kidney and heart following prolonged unilateral renal ischemia. Nephron Physiol. 2007;106:54–62. DOI: 10.1159/000103910.
8 - Ellison DH. Diuretic resistance: physiology and therapeutics. Semin Nephrol. 1999;19:581–597. <>.
9 - Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie BM, O’Connor CM, Rich MW, Stevenson LW, Wang Y, Young JB, Krumholz HM. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147:331–338. DOI: 10.1016/j.ahj.2003.08.012.
10 - Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260–269. DOI: 10.1056/NEJMoa051530.
11 - Blake P, Hasegawa Y, Khosla MC, Fouad-Tarazi F, Sakura N, Paganini EP. Isolation of “myocardial depressant factor(s)” from the ultrafiltrate of heart failure patients with acute renal failure. ASAIO J. 1996;42:M911–M915. PMID: 8945020 [PubMed—indexed for MEDLINE]
12 - Meyer TW, Hostetter TH. Uremia. N Engl J Med. 2007;357:1316–1325. DOI: 10.1056/NEJMra071313.
13 - Figueras J, Stein L, Diez V, Weil MH, Shubin H. Relationship between pulmonary hemodynamics and arterial pH and carbon dioxide tension in critically ill patients. Chest. 1976;70:466–472. DOI: 10.1378/chest.70.4.466.
14 - Brady JP, Hasbargen JA. Acid-base in renal failure: a review of the effects of correction of acidosis on nutrition in dialysis patients. Semin Dial. 2000;13:252–255. DOI: 10.1046/j.1525-139x.2000.00068.x.
15 - McCullough PA, Sandberg KR. Chronic kidney disease and sudden death: strategies for prevention. Blood Purif 2004;22:136–142. DOI: 10.1159/000074934.
16 - Pokhrel N, Maharjan N, Dhakal B, RR. Cardiorenal syndrome: A literature review. Exp Clin Cardiol. 2008;13:165–170. PMCID: PMC2663478
17 - Mahon NG, Blackstone EH, Francis GS, Starling RC 3rd, Young JB, Lauer MS. The prognostic value of estimated creatinine clearance alongside functional capacity in ambulatory patients with chronic congestive heart failure. J Am Coll Cardiol. 2002;40:1106–1113. DOI: 10.1016/S0735-1097(02)02125-3.
18 - Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006;47:76–84. DOI: 10.1016/j.jacc.2005.09.022.
19 - Strimbu K, Tavel JA. What are Biomarkers? Curr Opin HIV AIDS. 2010;5:463–466. DOI: 10.1097/COH.0b013e32833ed177.
20 - Biomarkers Definition Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Therapeutics. 2001;69:89–95. DOI: 10.1067/mcp.2001.113989.
21 - Cheeseman KH, Slater TF. An introduction to free radicals chemistry. Br Med Bull. 1993;49:481–493. PMID: 8221017 [PubMed—indexed for MEDLINE].
22 - Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol. 2001;54:176–186. DOI: 10.1136/jcp.54.3.176.
23 - Bagchi K, Puri S. Free radicals and antioxidants in health and disease. East Mediterranean Health J. 1998;4:350–360.
24 - Liu T, Stern A, Roberts LJ, Morrow JD. The isoprostanes: novel prostanglandin­like products of the free radical catalyzed peroxidation of arachidonic acid. J Biomed Sci. 1999;6:226–235. DOI: 10.1159/000025391.
25 - Rock CL, Jacob RA, Bowen PE. Update o biological characteristics of the antioxidant micronutrients—Vitamin C, Vitamin E and the carotenoids. J Am Diet Assoc. 1996;96:693–702. DOI: 10.1016/S0002-8223(96)00190-3.
26 - Mc Cord JM. The evolution of free radicals and oxidative stress. Am J Med. 2000;108:652–659. DOI: 10.1016/S0002-9343(00)00412-5.
27 - Nangaku M, Fujita T. Activation of the renin-angiotensin system and chronic hypoxia of the kidney. Hypertens Res. 2008;31:175–184. DOI: 10.1291/hypres.31.175
28 - Rubattu S, Mennuni S, Testa M, Mennuni M, Pierelli G, Pagliaro B, Gabriele E, Coluccia R, Autore C, Volpe M. Pathogenesis of chronic cardiorenal syndrome: is there a role for oxidative stress? Int J Mol Sci. 2013;14:23011–23032. DOI: 10.3390/ijms141123011.
29 - Bongartz LG, Cramer JM, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: “Guyton revisited.” Eur Heart Jour. 2005;26:11–17.DOI: 10.1093/eurheartj/ehi020.
30 - Donato V, Lacquaniti A, Cernaro V, Lorenzano G, Trimboli D, Buemi A, Lupica R, Buemi M. From Water to aquaretics: a legendary route. Cell Physiol Biochem. 2014; 33:1369–1388. DOI: 10.1159/000358704.
31 - Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RAK, Thaiss F. Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int. 2002;61:1986–1995. DOI: 10.1046/j.1523-1755.2002.00365.x.
32 - Wakui H, Dejima T, Tamura K, Uneda K, Azuma K, Maeda A, Ohsawa M, Kanaoka T, Azushima K, Kobayashi R, Matsuda M, Yamashita A, Umemura S. Activation of angiotensin II type 1 receptor-associated protein exerts an inhibitory effect on vascular hypertrophy and oxidative stress in angiotensin II-mediated hypertension. Cardiovasc Res. 2013; 100:511–519. DOI: 10.1093/cvr/cvt225.
33 - Schinzari F, Tesauro M, Rovella V, Adamo A, Mores N, Cardillo C. Co-existence of functional angiotensin II type 2 receptors mediating both vasoconstriction and vasodilation in humans. J Hypertension. 2011;29:1743–1748. DOI: 10.1097/HJH.0b013e328349ae0d.
34 - Pernomian L, Gomes MS, Restini CBA, Ramalho LNZ, Tirapelli CR, Oliveira AM. The role of reactive oxygen species in the modulation of the contraction induced by angiotensin II in carotid artery from diabetic rat. Eur Jour of Pharmacol. 2012;678:15–25. DOI: 10.1016/j.ejphar.2011.12.036.
35 - Patel KP, Mayhan WG, Bidasee KR, Zheng H. Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: role of superoxide anion. Am J Physiol Regul Integr Comp Physiol. 2011;300:311–320. DOI: 10.1152/ajpregu.00246.2010.
36 - Lavoie J, Sigmund CD. Minireview: overview of the renin-angiotensin system—endocrine and paracrine system. Endocrinology. 2003;144:2179–2183. DOI: 10.1210/en.2003-0150.
37 - Rahimi Z. The role of renin angiotensin aldosterone system genes in diabetic nephropathy. Can J Diabetes. 2015; pii:S1499-2671(15)00627-9. DOI: 10.1016/j.jcjd.2015.08.016.
38 - Reis WL, Saad WA, Camargo LA, Elias LLK, Rodrigues JA. Central nitrergic system regulation of neuroendocrine secretion, fluid intake and blood pressure induced by angiotensin-II. Behav Brain Funct. 2010;6:64–72. DOI: 10.1186/1744-9081-6-64.
39 - Touyz RM, Berry C. Recent advances in angiotensin II signaling. Braz J Med Biol Res. 2002;35:1001–1015. DOI: 10.1590/S0100-879X2002000900001.
40 - Berk BC, Corson MA. Angiotensin II signal transduction in vascular smooth muscle. Role of tyrosine kinases. Circ Res. 1997;80:607–616. DOI: 10.1161/01.RES.80.5.607.
41 - Calò LA, Schiavo S, Davis PA, Pagnin E, Mormino P, D’Angelo A, Pessina AC. Angiotensin II signaling via type 2 receptors in a human model of vascular hyporeactivity: implications for hypertension. J Hypertension 2010; 28:111–118. DOI: 10.1097/HJH.0b013e328332b738.
42 - Herichova I, Szantoova K. Renin-angiotensin system: upgrade of recent knowledge and perspectives. Endocr Regul. 2014;47:39–52. DOI: 10.4149/endo_2013_01_39.
43 - Guimarães PB, Alvarenga EC, Siqueira PD, Paredes-Gamero EJ, Sabatini RA, Morais RLT, Reis RI, Santos EL, Teixeira LGD, Casarini DE, Martin RP, Shimuta SI, Carmona AK, Nakaie CR, Jasiulionis MG, Ferreira AT, Pesquero JL, Oliveira SM, Bader M, Costa-Neto CM, Pesquero JB. Angiotensin II binding to angiotensin I-converting enzyme triggers calcium signaling. Hypertension. 2011;57:965–972. DOI: 10.1161/HYPERTENSIONAHA.110.167171.
44 - Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11–34. DOI: 0031-6997/11/5201-0011$03.00/0.
45 - Wolf G, Schneider A, Helmchen UM, Stahl RAK. AT1-receptor antagonists abolish glomerular MCP-1 expression in a model of mesangial proliferative glomerulonephritis. Exp Nephrol. 1998;6:112–120. DOI: 10.1159/000020513.
46 - Ruiz-Ortega M, Rupérez M, Esteban V, Sánchez-López E, Rodríguez-Vita J, Carvajal G, Egido J. Inflammation and chronic disease, 2006:1–25 ISBN: 81-7895-199-1. Editors: P. Esbrit and Mª. V. Alvarez-Arroyo. Transworld Research Network 37/661 (2), Fort P.O., Trivandrum-695 023, Kerala, India.
47 - Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. AngiotensinII induces monocyte chemo attractant protein-1 gene expression in rat vascular smooth muscle cells. Cir Res. 1998;83:952–959. DOI: 10.1161/01.RES.83.9.952.
48 - Wolf G, Ziyadeh FN, Thaiss F, Tomaszewski J, Caron RJ, Wenzel U, Zahner G, Helmchen U, Stahl RAK. Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest. 1997;100:1047–1058. DOI: 0021-9738/97/09/1047/12.
49 - Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW. Temporal dispersion of activation of phospholipase C-beta 1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits. J Biol Chem. 1998;273:19772–19777. DOI: 10.1074/jbc.273.31.19772.
50 - Alexander RW, Brock TA, Gimbrone-Jr MA, Rittenhouse SE. Angiotensin increases inositol trisphosphate and calcium in vascular smooth muscle. Hypertension. 1985;7:447–451. DOI: 10.1161/01.HYP.7.3.447.
51 - Ushio-Fukai M, Alexander RW, Akers M, Lyons PR, Lassègue B & Griendling KK. Angiotensin II receptor coupling to phospholipase D is mediated by the ßg subunits of heterotrimeric G proteins in vascular smooth muscle cells. Mol Pharmacol. 1999;55:142–149. DOI: 10.1124/mol.55.1.142.
52 - Dhalla NS, Xu Y-J, Sheu S-S, Tappia PS, Panagia V. Phosphatidic acid: a potential signal transducer for cardiac hypertrophy. J Mol Cell Cardiol. 1997;29:2865–2871. DOI: 10.1006/jmcc.1997.0522.
53 - Touyz RM, Schiffrin EL. Ang II–stimulated superoxide production is mediated via phospholipase d in human vascular smooth muscle cells. Hypertension. 1999;34:976–982. DOI: 10.1161/01.HYP.34.4.976.
54 - Billah MM. Phospholipase D and cell signaling. Curr Opin Immunol. 1993;5:114–123. DOI: 10.1016/0952-7915(93)90090-F.
55 - Bonventre JV. Phospholipase A2 and signal transduction. J Am Soc Nephrol. 1992;3:128–150.
56 - Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, and Griendling KK. Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res. 2002;91:406—413. DOI: 10.1161/01.RES.0000033523.08033.16.
57 - Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, Pagano PJ, Schiffrin EL. Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res. 2002; 90:1205—1213. DOI: 10.1161/01.RES.0000020404.01971.2F.
58 - Lassegue B, Alexander RW, Clark M, Griendling KK. Angiotensin II-induced phosphatidylcholine hydrolysis in cultured vascular smooth-muscle cells. Regulation and localization. Biochem J. 1991;276: 19–25.
59 - Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol. 2003;285:R277—R297. DOI: 10.1152/ajpregu.00758.2002.
60 - Touyz RM, Schiffrin EL. Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. J Hypertens. 2001;19:1245–1254. PMID: 11446714 [PubMed—indexed for MEDLINE].
61 - Zafari AM, Ushio-Fukai M, Minieri CA, Akers M, Lassegue B, Griendling KK. Arachidonic acid metabolites mediate angiotensin II-induced NADH/NADPH oxidase activity and hypertrophy in vascular smooth muscle cells. Antioxid Redox Signal. 1999;1:167–179. PMID: 11228745 [PubMed—indexed for MEDLINE].
62 - Matsusaka T, Ichikawa I. Biological functions of angiotensin and its receptors. Annu Rev Physiol. 1997;59:395–412. DOI: 10.1146/annurev.physiol.59.1.395.
63 - Berk BC, Corson M. Angiotensin II signal transduction in vascular smooth muscle. Role of tyrosine kinases. Circul Res. 1997;80:607–616. DOI: 10.1161/01.RES.80.5.607.
64 - Sayeski PP, Ali MS, Harp JB, Marrero MB, Bernstein KE. Phosphorylation of p130Cas by angiotensin II is dependent on c-Src, intracellular Ca2+, and protein kinase C. Circul Res. 1998;82:1279–1288. DOI: 10.1161/01.RES.82.12.1279.
65 - Marrero MB, Schieffer B, Li B, Sun J, Harp JB, Ling BN. Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. J Biol Chem. 1997;272:24684–24690. DOI: 10.1074/jbc.272.39.24684.
66 - Leduc I, Meloche S. Angiotensin II stimulates tyrosine phosphorylation of the focal adhesion protein paxillin in aortic smooth muscle cells. J Biol Chem. 1995;270:4401–4404. DOI: 10.1074/jbc.270.9.4401.
67 - Takahashi T, Kawahara Y, Taniguchi T, Yokoyama M. Tyrosine phosphorylation and association of p130Cas and c-Crk II by Ang II in vascular smooth muscle cells. Am J Physiol. 1998;274:H1059–H1065.
68 - Takahashi T, Taniguchi T, Konishi H, Kikkawa U, Ishikawa Y, Yokoyama M. Activation of Akt/PKB after stimulation with Ang II in vascular smooth muscle cells. Am J Physiol. 1999;276:H1927–H1934.
69 - Touyz RM, He G, Deng LY, Schiffrin EL. Role of extracellular signal-regulated kinases in angiotensin II—stimulated contraction of smooth muscle cells from human resistance arteries. Circulation. 1999;99:392–399. DOI: 10.1161/01.CIR.99.3.392.
70 - Touyz RM, He G, El Mabrouk M, Diep Q, Mardigyan V, Schiffrin EL. Differential activation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen activated-protein kinase by AT1 receptors in vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats. J Hypertens. 2001;19:553–559. DOI: 10.1097/00004872-200103001-00006.
71 - Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997;9:180–186. DOI: 10.1016/S0955-0674(97)80061-0.
72 - Liao DF, Monia B, Dean N, Berk BC. Protein kinase C-zeta mediates angiotensin II activation of ERK1/2 in vascular smooth muscle cells. J Biol Chem. 1997;272:6146–6150. DOI: 10.1074/jbc.272.10.6146.
73 - Ushio-Fukai M, Alexander RW, Akers M, Griendling KK. Mitogen activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. Role in vascular smooth muscle cell hypertrophy. J Biol Chem. 1998;273:15022–15029.DOI: 10.1074/jbc.273.24.15022.
74 - Laufs U, Liao JK. Targeting Rho in cardiovascular disease. Circul Res. 2000;87:526–528. DOI: 10.1161/01.RES.87.7.526.
75 - San Martin A, Griendling KK. NADPH oxidases: progress and opportunities. Antioxid Redox Signal. 2014;20:2692–2694. DOI: 10.1089/ars.2014.5947.
76 - Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJV, Ponikowski P, Poole-Wilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388–2442. DOI: 10.1093/eurheartj/ehn309.
77 - Silverberg D, Wexler D, Blum M, Schwartz D, Adrian I. The association between congestive heart failure and chronic renal disease. Curr Opin Nephrol Hypertens. 2004;13:163–170. PMID: 15202610 [PubMed—indexed for MEDLINE].
78 - Joles JA, Koomans HA. Causes and consequences of increased sympathetic activity in renal disease. Hypertension. 2004;43:699–706. DOI: 10.1161/01.HYP.0000121881.77212.b1.
79 - Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341:577–585. DOI: 10.1056/NEJM199908193410806.
80 - Guyton AC. The surprising kidney-fluid mechanism for pressure control—its infinite gain. Hypertension. 1990;16:725–730. DOI: 10.1161/01.HYP.16.6.725.
81 - Bongartz LG, Cramer MJ, Braam B: The cardiorenal connection. Hypertension. 2004;43:e14. DOI: 10.1161/01.HYP.0000118521.06245.b8.
82 - Viswanathan G, Scott G. The cardiorenal syndrome: making the connection. Int J Nephrol. 2001; ID:283137.
83 - Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med. 2004;116:263–272. DOI: 10.1016/j.amjmed.2003.09.034.
84 - Cadnapaphornchai MA, Gurevich AK, Weinberger HD, Schrier R.W. Pathophysiology of sodium and water retention in heart failure. Cardiology. 2001;96:122–131. DOI: 10.1159/000047396.
85 - Braam B, Koomans HA. Renal responses to antagonism of the renin-angiotensin system. Curr Opin Nephrol Hypertens. 1996;5:89–96. PMID: 8834166 [PubMed—indexed for MEDLINE]
86 - Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–1148. DOI: 10.1161/01.RES.74.6.1141.
87 - Pedruzzi E, Guichard C, Ollivier V, Driss F, Fay M, Prunet C, Marie JC, Pouzet C, Samadi M, Elbim C, O’Dowd Y, Bens M, Vandewalle A, Gougerot-Pocidalo MA, Lizard G, Ogier-Denis E. NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol. 2004;24:10703–10717. DOI: 10.1128/MCB.24.24.10703-10717.2004.
88 - Zhang H, Schmeisser A, Garlichs CD, Plotze K, Damme U, Mugge A, Daniel WG. Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res. 2009;44:215–222. DOI: 10.1016/S0008-6363(99)00183-2.
89 - Hishikawa K, Luscher TF. Pulsatile stretch stimulates superoxide production in human aortic endothelial cells. Circulation. 1997;96:3610–3616. DOI: 10.1161/01.CIR.96.10.3610.
90 - Hishikawa K, Oemar BS, Yang Z, Luscher TF. Pulsatile stretch stimulates superoxide production and activates nuclear factor-kB in human coronary smooth muscle cells. Circ Res. 1997;81:797–803. DOI: 10.1161/01.RES.81.5.797.
91 - Mohazzab KM, Wolin MS. Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol. 1994;267:H2568–H2572. PMID: 7810685 [PubMed—indexed for MEDLINE].
92 - Rajagopalan S, Kurz S, Munzel T, Tarpey NI, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923. DOI: 10.1172/JCI118623.
93 - Ushio-Fukai M, Zafari AM, Fukui T Ishizaka N, Griendling KK. p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem. 1996;271:23317–23321. DOI: 10.1074/jbc.271.38.23317.
94 - Chabrashvili T, Kitiyakara C, Blau J, Karber A, Aslam S, Welch WJ, Wilcox CS. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol. 2003;285:R117–R124. DOI: 10.1152/ajpregu.00476.2002.
95 - Nakagami H, Takemoto M, Liao JK. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy. J Mol Cell Cardiol. 2003;35:851–859.DOI: 10.1016/S0022-2828(03)00145-7.
96 - Radeke HH, Cross AR, Hancock JT, Jones OT, Nakamura Ni, Kaever V, Resch K. Functional expression of NADPH oxidase components (α- and β-subunits of cytochrome b558 and 45-kDa flavoprotein) by intrinsic human glomerular mesangial cells. J Biol Chem. 1991;266:21025–21029. PMID: 1657945 [PubMed—indexed for MEDLINE]
97 - Fukui T, Lassegue B, Kai H, Alexander RW, Griendling KK. Cytochrome b-558 α-subunit cloning and expression in rat aortic smooth muscle cells. Biochim Biophys Acta. 1995;1231:215–219. DOI: 10.1016/0005-2728(95)00098-4.
98 - Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999;401:79–82. DOI: 10.1038/43459.
99 - Jones SA, O’Donnell VB, Wood JD, Broughton JP, Hughes EJ, Jones OT. Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol. 1996;271:H1626–H1634. PMID: 8897960 [PubMed—indexed for MEDLINE].
100 - Greiber S, Munzel T, Kastner S, Muller B, Schollmeyer P, Pavenstädt H. NAD(P)H oxidase activity in cultured human podocytes: effects of adenosine triphosphate. Kidney Int. 1998;53:654–663.DOI: 10.1046/j.1523-1755.1998.00796.x.
101 - Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 2000;9:8010–8014. DOI: 10.1073/pnas.130135897.
102 - Pagano PJ, Clark JK, Cifuentes-Pagano ME, Clark SM, Callis GM, Quinn MT. Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc Natl Acad Sci U S A. 1997;94:14483–14488.
103 - Babior BM. NADPH oxidase: an update. Blood. 1999;93:1464–1476. PMID: 10029572 [PubMed—indexed for MEDLINE]. 0006-4971/99/9305-0033$3.00/0.
104 - Katoh M, Egashira K, Usui M, Ichiki T, Tomita H, Shimokawa H, Rakugi H, Takeshita A. Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats. Circ Res. 1998;83:743–751. DOI: 10.1161/01.RES.83.7.743.
105 - Chabrashvili T, Tojo A, Onozato ML, Kitiyakara C, Quinn MT, Fujita T, Welch WJ, Wilcox CS. Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension. 2002;39:269–274. DOI: 10.1161/hy0202.103264.
106 - Racusen LC, Prozialeck DH, Solez K. Glomerular epithelial cell changes after ischemia or dehydration. Possible role of angiotensin II. Am J Pathol. 1984;114:157–163. PMCID: PMC1900389.
107 - Liebau MC, Lang D, Bohm J, Endlich N, Bek MJ, Witherden I, Mathieson PW, Saleem MA, Pavenstädt H, Fischer KG. Functional expression of the renin-angiotensin system in human podocytes. Am J Physiol Renal Physiol. 2006;290:F710–F719. DOI: 10.1152/ajprenal.00475.2004.
108 - Hoffmann S, Podlich D, Hahnel B, Kriz W, Gretz N. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol. 2004;15:1475–1487. DOI: 10.1097/01.ASN.0000127988.42710.A7.
109 - Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49:355–364. DOI: 10.1161/01.HYP.0000255636.11931.a2.
110 - Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, Fujita T. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol. 2006;17:3438–3446. DOI: 10.1681/ASN.2006080944.
111 - Beswick RA, Zhang H, Marable D, Catravas JD, Hill WD, Webb RC. Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension. 2001;37:781–781. DOI: 10.1161/01.HYP.37.2.781.
112 - Rapp JP. Dahl salt-susceptible and salt-resistant rats. Hypertension. 1982;4:753–763.
113 - Tojo A, Onozato ML, Kobayashi N, Goto A, Matsuoka H, Fujita T. Angiotensin II and oxidative stress in Dahl Salt-sensitive rat with heart failure. Hypertension. 2002;40:834–839. DOI: 10.1161/01.HYP.0000039506.43589.D5.
114 - Heymes C, Bendall JK, Ratajczak P, Cave AC, Samuel JL, Hasenfuss G, Shah AM. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol. 2003;41:2164–2171. DOI: 10.1016/S0735-1097(03)00471-6.
115 - Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, Tatge H, Drexler H. Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation. 2001;103:799–805. DOI: 10.1161/01.CIR.103.6.799.
116 - Ruiz-Ortega M, Lorenzo O, Egido J. Angiotensin III increases MCP-1 and activates NF-kappaB and AP-1 in cultured mesangial and mononuclear cells. Kidney Int. 2000;57:2285–2298. DOI: 10.1046/j.1523-1755.2000.00089.x.
117 - Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 2000;20:645–651. DOI: 10.1161/01.ATV.20.3.645.
118 - Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992;262:E763–E778.
119 - Converse RL Jr, Jacobsen TN, Toto RD, Jost CMT, Cosentino F, Fouad-Tarazi F, Victor RG. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992;327:1912–1918. DOI: 10.1056/NEJM199212313272704.
120 - Ligtenberg G, Blankestijn PJ, Oey PL, Klein IHH, Dijkhorst-Oei LT, Boomsma F, Wieneke GH, van Huffelen AC, Koomans HA. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med. 1999;340:1321–1328. DOI: 10.1056/NEJM199904293401704.
121 - Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. J Am Soc Nephrol. 2003;14:425–430. DOI: 10.1097/01.ASN.0000045049.72965.B7.
122 - Zhang W, Huang BS, Leenen FH. Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction. Am J Physiol. 1999;276:H1608–H1615. PMID: 10330245 [PubMed—indexed for MEDLINE].
123 - Lin HH, Chen CH, Hsieh WK, Chiu TH, Lai CC. Hydrogen peroxide increases the activity of rat sympathetic preganglionic neurons in vivo and in vitro. Neuroscience. 2003;121:641–647. DOI: 10.1016/S0306-4522(03)00517-7.
124 - Shokoji T, Nishiyama A, Fujisawa Y, Hitomi H, Kiyomoto H, Takahashi N, Kimura S, Kohno M, Abe Y. Renal sympathetic nerve responses to tempol in spontaneously hypertensive rats. Hypertension. 2003;41:266–273. DOI: 10.1161/01.HYP.0000049621.85474.CF.
125 - Chen L, Knowlton AA. Mitochondrial dynamics in heart failure. Congest Heart Fail. 2010;17:257–261. DOI: 10.1016/j.bbamcr.2012.03.008.
126 - Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev. 2002;7:115–130. DOI: 10.1023/A:1015320423577.
127 - Beer M, Seyfarth T, Sandstede J, Landschütz W, Lipke C, Köstler H, von Kienlin M, Harre K, Hahn D, Neubauer S. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol. 2002;40:1267–1274. DOI: 10.1016/S0735-1097(02)02160-5.
128 - Conway MA, Allis, J. Ouwerkerk R, Niioka T, Rajagopalan B, Radda GK. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet. 1991;338:973–976. DOI: 10.1016/0140-6736(91)91838-L.
129 - Tian R, Nascimben L, Kaddurah-Daouk R, Ingwall JS. Depletion of energy reserve via the creatine kinase reaction during the evolution of heart failure in cardiomyopathic hamsters. J Mol Cell Cardiol. 1996;28:755–765. DOI: 10.1006/jmcc.1996.0070.
130 - Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, Iwanaga Y, Narazak M, Matsuda T, Soga T, Kita T, Kimura T, Shioi T. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail. 2010;3:420–430. DOI: 10.1161/CIRCHEARTFAILURE.109.888479.
131 - Lei B, Lionetti V, Young ME, Chandler MP, d’Agostino C, Kang E, Altarejos M, Matsuo K, Hintze TH, Stanley WC, Recchia FA. Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J Mol Cell Cardiol. 2004;36:567–576. DOI: 10.1016/j.yjmcc.2004.02.004.
132 - Katz AM, Konstam MA. Heart failure : pathophysiology, molecular biology, and clinical management (2nd ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009. ISBN 978-0781769464.
133 - Scheubel RJ, Tostlebe M, Simm A, Rohrbach S, Prondzinsky R, Gellerich FN, Silber RE, Holtz J. Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol. 2002;40:2174–2181. DOI: 10.1016/S0735-1097(02)02600-1.
134 - Lemieux H, Semsroth S, Antretter H, Höfer D, Gnaiger E. Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart. Int J Biochem Cell Biol. 2011;43:1729–1738. DOI: 10.1016/j.biocel.2011.08.008.
135 - Buchwald A, Till H, Unterberg C, Oberschmidt R, Figulla HR, Wiegand V. Alterations of the mitochondrial respiratory chain in human dilated cardiomyopathy. Eur Heart J. 1990;11:509–516. 509-516.
136 - Marin-Garcia J, Goldenthal J, Mo GW. Mitochondrial pathology in cardiac failure. Cardiovasc Res. 2001;49:17–26. DOI: 10.1016/S0008-6363(00)00241-8.
137 - Rosca MG, Vazquez EJ, Kerner J, Parland W, Chandler MP, Stanley W, Sabbah HN, Hoppel CL. Cardiac mitochondria in heart failure: Decrease in respirasomes and oxidative phosphorylation. Cardiovasc Res. 2008;80:30–39. DOI: 10.1093/cvr/cvn184.
138 - Touyz RM, Briones AM, Sedeek M, Burger D, Montezano AC. NOX Isoforms and reactive oxygen species in vascular health. Mol Interv. 2011;11:27–35. DOI: 10.1124/mi.11.1.5.
139 - Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Suzuki T, Maeta H, Abe Y. Role of NAD (P) H oxidase-and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. Hypertension. 2005;45:860–866. DOI: 10.1161/01.HYP.0000163462.98381.7f.
140 - Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintrón M, Chen T, Marcinek DJ, Dorn GW, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS. Mitochondrial oxidative stress mediates angiotensin II–induced cardiac hypertrophy and Gαq overexpression–induced heart failure. Novelty and significance. Circ Res. 2011;108:837–846. DOI: 10.1161/CIRCRESAHA.110.232306.
141 - Marín-García J, Akhmedov AT, Moe GW. Mitochondria in heart failure: the emerging role of mitochondrial dynamics. Heart Fail Rev. 2013;18:439–456. DOI: 10.1007/s10741-012-9330-2.
142 - Jackson G, Gibbs CR, Davies MK, Lip GYH. ABC of heart failure: pathophysiology. BMJ. 2000;320:167–170. DOI: 10.1136/bmj.320.7228.167.
143 - Rosca MG, Hoppel CL. New aspects of impaired mitochondrial function in heart failure. J Bioenerg Biomembr. 2009;41:107–112. DOI: 10.1007/s10863-009-9215-9.
144 - Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol. 2001;280:C53–C60. PMID: 11121376 [PubMed—indexed for MEDLINE].
145 - Aranapakam V, Grosu GT, Davis JM, Hu B, Ellingboe J, Baker JL, Skotnicki JS, Zask A, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling RJ. Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. Med Chem. 2003; 46:2361–2375. DOI: 10.1021/jm0205548.
146 - Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler O, Schlotte V, Weithmann KU, Wendt KU. Structural basis for the highly selective inhibition of MMP-13. Chem Biol. 2005;12:181–189. DOI: 10.1016/j.chembiol.2004.11.014.
147 - Amin EA, Welsh WJ. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: applying a “divide and conquer” strategy. J Med Chem. 2001;44:3849–3855. DOI: CHEMBL1134678.
148 - Raspollini MR, Castiglione F, Degl’Innocenti DR, Garbini F, Coccia ME, Taddei GL. Difference in expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in patients with persistent ovarian cysts. Fertil Steril. 2005;84:1049–1052. DOI: 10.1016/j.fertnstert.2005.02.058.
149 - Venkatesan AM, Davis JM, Grosu GT, Baker J, Zask A, Levin JI, Ellingboe J, Skotnicki JS, DiJoseph JF, Sung A, Jin G, Xu W, McCarthy DJ, Barone D. Synthesis and structure–activity relationships of 4-alkynyloxy phenyl sulfanyl, sulfinyl, and sulfonyl alkyl hydroxamates as tumor necrosis factor-α converting enzyme and matrix metalloproteinase inhibitor. J Med Chem. 2004;47:6255–6269. DOI: 10.1021/jm040086x.
150 - Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991;5:2145–2154.
151 - Dounousi E, Papavasiliou E, Makedou A, Ioannou K, Katopodis KP, Tselepis A, Siamopoulos KC, Tsakiris D. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis. 2006;48:752–760. DOI: 10.1053/j.ajkd.2006.08.015.
152 - Oberg BP, McMenamin E, Lucas FL, McMonagle E, Morrow J, Ikizler TA, Himmelfarb J. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 2004;65:1009–1016. DOI: 10.1111/j.1523-1755.2004.00465.x.
153 - Nerpin E, Helmersson-Karlqvist J, Risérus U, Sundström J, Larsson A, Jobs E, Basu S, Ingelsson E, Arnlöv. J. Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study. BMC Res. Notes 2012;5:537. DOI: 10.1186/1756-0500-5-537.
154 - Shlipak MG, Fried LF, Crump C, Bleyer AJ, Manolio TA, Tracy RP, Furberg CD, Psaty BM. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003;107:87–92. DOI: 10.1161/01.CIR.0000042700.48769.59.
155 - Stuveling EM, Hillege HL, Bakker SJ, Gans RO, de Jong PE, de Zeeuw D. C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int. 2003;63:654–661. DOI: 10.1046/j.1523-1755.2003.00762.x.
156 - Ikizler TA, Morrow JD, Roberts LJ, Evanson JA, Becke B, Hakim RM, Shyr Y, Himmelfarb J. Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients. Clin Nephrol. 2002;58:190–197. DOI: 10.5414/CNP58190.
157 - Nagase M. Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome. Clin Exp Nephrol. 2010;14:303–314. DOI: 10.1007/s10157-010-0298-8.
158 - Raij L. Workshop: hypertension and cardiovascular risk factors: role of the angiotensin II-nitric oxide interaction. Hypertension. 2001;37:767–773. DOI: 10.1161/01.HYP.37.2.767.
159 - Zou AP, Li N, Cowley AW. Production and actions of superoxide in the renal medulla. Hypertension 2001;37:547–553. DOI: 10.1161/01.HYP.37.2.547.
160 - Chabrashvili T, Tojo A, Onozato ML, Kitiyakara C, Quinn MT, Fujita T, Welch WJ, Wilcox CS. Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension. 2002;39:269–274. DOI: 10.1161/hy0202.103264.
161 - Geiszt M, Kopp JB, Várnai P, Leto TL. Identification of renox, an NAD (P) H oxidase in kidney. Proc Natl Acad Sci U S A. 2000;97:8010–8014. DOI: 10.1073/pnas.130135897.
162 - Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, Hattori M, Sakaki Y, Sumimoto H. A novel superoxide-producing NAD (P) H oxidase in kidney. J Biol Chem. 2001;276:1417–1423. DOI: 10.1074/jbc.M007597200.
163 - Cheng G, Cao Z, Xu X, Meir EGV, Lambeth JD. Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene. 2001;269:131–140. DOI: 10.1016/S0378-1119(01)00449-8.
164 - Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev. 2007;87:245–313. DOI: 10.1152/physrev.00044.2005.
165 - Gorin Y, Ricono JM, Kim NH, Bhandari B, Choudhury GG, Abboud HE. Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am J Physiol Ren Physiol. 2003;285: F219–F229. DOI: 10.1152/ajprenal.00414.2002.
166 - Raij L. Nitric oxide and cardiovascular and renal effects. Osteoarthr Cartil. 2008;16:S21–S26. DOI: 10.1016/S1063-4584(08)60009-6.
167 - Mayer B, Pfeiffer S, Schrammel A, Koesling D, Schmidt K, Brunner F. A new pathway of nitric oxide/cyclic GMP signaling involving S-nitrosoglutathione. J Biol Chem.1998;273:3264–3270. DOI: 10.1074/jbc.273.6.3264.
168 - Gladwin MT, Schechter AN, Kim-Shapiro DB, Patel RP, Hogg N, Shiva S, Cannon RO, Kelm M, Wink DA, Espey MG, Oldfield EH, Pluta RM, Freeman BA, Lancaster Jr JR, Feelisch M, Lundberg JO. The emerging biology of the nitrite anion. Nat Chem Biol 2005;1:308–314. DOI: 10.1038/nchembio1105-308.
169 - Kelm M, Dahmann R, Wink D, Feelisch M. The nitric oxide/superoxide assay. Insights into the biological chemistry of the NO/O-2. interaction. J Biol Chem 1997;272:9922–9932.
170 - Wilcox CS. Redox regulation of the afferent arteriole and tubuloglomerular feedback. Acta Physiol Scand. 2003;179,217–223. DOI: 10.1046/j.0001-6772.2003.01205.x.
171 - López B, Salom MG, Arregui B, Valero F, Fenoy FJ. Role of superoxide in modulating the renal effects of angiotensin II. Hypertension. 2003;42:1150–1156. DOI: 10.1161/01.HYP.0000101968.09376.79.
172 - Liaudet L, Soriano FG, Szabó C. Biology of nitric oxide signaling. Crit Care Med. 2000;28:N37–N52. DOI: 10.1097/00003246-200004001-00005.
173 - Schnackenberg CG. Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol. 2002;282:R335–R342. DOI: 10.1152/ajpregu.00605.2001.
174 - Lodha S, Dani D, Mehta R, Bhaskaran M, Reddy K, Ding G, Singhal PC. Angiotensin II-induced mesangial cell apoptosis: role of oxidative stress. Mol Med. 2002;8:830–840. PMC2039960/pdf/12606818.pdf.
175 - Gorin Y, Ricono J, Wagner B, Kim N, Bhandari B, Choudhury G, Abboud H. Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells. Biochem J. 2004;381:231–239. DOI: 10.1042/BJ20031614.
176 - Rhyu DY, Yang Y, Ha H, Lee GT, Song JS, Uh ST, Lee HB. Role of reactive oxygen species in TGF-β1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol. 2005;16:667–675. DOI: 10.1681/ASN.2004050425.
177 - Thiery JP, Sleeman JP. Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–142. DOI: 10.1038/nrm1835.
178 - Ng YY, Huang TP, Yang WC, Chen ZP, Yang AH, Mu W, Nikolic-Paterso DJ, Atkins RC, Lan HY. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int. 1998;54:864–876. DOI: 10.1046/j.1523-1755.1998.00076.x.
179 - Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Investig. 2002;110:341–350. DOI: 10.1172/JCI15518.
180 - Napoli C, Casamassimi A, Crudele V, Infante T, Abbondanza C. Kidney and heart interactions during cardiorenal syndrome: a molecular and clinical pathogenic framework. Future Cardiol. 2011;7:485–497. DOI: 10.2217/fca.11.24.
181 - Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. 2009;119:1420–1428. DOI: 10.1172/JCI39104.
182 - Yoshikawa M, Hishikawa K, Marumo T, Fujita T. Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-β1 in human renal epithelial cells. J Am Soc Nephrol. 2007;18:58–65. DOI: 10.1681/ASN.2005111187.
183 - Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001;159:1465–1475. DOI: 10.1016/S0002-9440(10)62533-3.
184 - Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension. 2001;38:635–638. DOI: 10.1161/hy09t1.094234.
185 - Dorsam G, Tahe MM, Valerie KC, Kuemmerle NB, Chan JC, Franson RC. Diphenyleneiodium chloride blocks inflammatory cytokine-induced up-regulation of group IIA phospholipase A2 in rat mesangial cells. J Pharmacol Exp Ther. 2000;292:271–279.
186 - Satriano JA, Shuldiner M, Hora K, Xing Y, Shan Z, Schlondorff D. Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Investig 1993;92:1564–1571. DOI: 10.1172/JCI116737.
187 - Feng L, Xia Y, Garcia GE, Hwang D, Wilson CB. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. J Clin Investig. 1995;95:1669–1675. DOI: 10.1172/JCI117842.
188 - Cui XL, Douglas JG. Arachidonic acid activates c-jun N-terminal kinase through NADPH oxidase in rabbit proximal tubular epithelial cells. Proc Natl Acad Sci USA. 1997;94:3771–3776. PMCID: PMC20516.
189 - Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, Bouillaud F, and Ricquier D. The biology of mitochondrial uncoupling proteins. Diabetes. 2004;53:130–135. DOI: 10.2337/diabetes.53.2007.S130.
190 - Di Castro, S.; Scarpino, S.; Marchitti, S.; Bianchi, F.; Stanzione, R.; Cotugno, M.; Sironi, L.; Gelosa, P.; Duranti, E.; Ruco, L., Volpe M, Rubattu S. Differential modulation of UCP2 in kidneys of stroke-prone spontaneously hypertensive rats under high salt/low potassium diet. Hypertension 2013, 61, 534–541. DOI: 10.1161/HYPERTENSIONAHA.111.00101.
191 - Yoshida T, Kato K, Fujimak T, Yokoi K, Oguri M, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Tanaka M, Nozawa Y, Kimura G, Yamada Y. Association of genetic variants with chronic kidney disease in Japanese individuals. Clin J Am Soc Nephrol. 2009;4:883–890. DOI: 10.2215/CJN.04350808.
192 - Metra M, Davison B, Bettari L, Sun H, Edwards C, Lazzarini V, Piovanelli B, Carubelli V, Bugatti S, Lombardi C, Cotter G, Dei Cas L. Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circ Heart Fail. 2012;5:54–62. DOI: 10.1161/CIRCHEARTFAILURE.111.963413.
193 - Bayeva M, Gheorghiade M, Ardehali H. Mitochondria as a therapeutic target in heart failure. J Am Coll Cardiol. 2013;61:599–610. DOI: 10.1016/j.jacc.2012.08.1021.
194 - Chen K, Keaney JF. Evolving concepts of oxidative stress and reactive oxygen species in cardiovascular disease. Curr Atheroscler Rep. 2012;14:476–483. DOI: 10.1007/s11883-012-0266-8.
195 - Fassett RG, Venuthurupalli SK, Gobe GC, Coombes JS, Cooper MA, Hoy WE. Biomarkers in chronic kidney disease: a review. Kidney Int. 2011;80:806–821; DOI: 10.1038/ki.2011.198.
196 - Sun M, Dawood F, Wen WH, Chen M, Dixon I, Kirshenbaum LA, Liu PP. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction. Circulation. 2004;110:3221–3228. DOI: 10.1161/01.CIR.0000147233.10318.23.
197 - Liu P, Sun M, Sader S. Matrix metalloproteinases in cardiovascular disease. Can J Cardiol. 2006;22:25B–30B. PMCID: PMC2780831.
198 - Stewart JA Jr, Wei CC, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi PA, Janicki JS, Dell'Italia LJ. Cardiac mast cell- and chymase-mediated matrix metalloproteinase activity and left ventricular remodeling in mitral regurgitation in the dog. J Mol Cell Cardiol. 2003;35:311–319. DOI: 10.1016/S0022-2828(03)00013-0.
199 - Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure relation to ventricular and myocyte function. Circ Res. 1998;82:482–495. DOI: 10.1161/01.RES.82.4.482.
200 - Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori F, Ikeuchi M, Kubota T, Sunagawa K, Hasegawa Y, Kurihara T, Oikawa S, Kinugawa S, Tsutsui H. Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation. 2006;113:1779–1786. DOI: 10.1161/CIRCULATIONAHA.105.582239.
201 - Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–219. DOI: 10.1016/S0092-8674(04)00046-7.
202 - Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;412:95–99. DOI: 10.1038/35083620.
203 - Kwon SH, Pimentel DR, Remondino A, Sawyer DB, Colucci WS. H2O2 regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. J Mol Cell Cardiol. 2003;35:615–621. DOI: 10.1016/S0022-2828(03)00084-1.
204 - Chaanine AH, Jeong D, Liang L, Chemaly ER, Fish K, Gordon RE, Hajjar RJ. JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis. 2012;3:265. DOI: 10.1038/cddis.2012.5.
205 - Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA, Lavandero S. Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis. 2011;2: e244. DOI: 10.1038/cddis.2011.130.
206 - Vacek, T.P.; Vacek, J.C.; Tyagi, S.C. Mitochondrial mitophagic mechanisms of myocardial matrix metabolism and remodelling. Arch Physiol Biochem. 2012;118:31–42. DOI: 10.3109/13813455.2011.635660. Epub 2011 Dec 19.
207 - Anatoliotakis N, Deftereos S, Bouras G, Giannopoulos G, Tsounis D, Angelidis C, Kaoukis A, Stefanadis C. Myeloperoxidase: expressing inflammation and oxidative stress in cardiovascular disease. Curr Top Med Chem. 2013;13:115–138. DOI: 10.2174/1568026611313020004.
208 - Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2005; 25:1102–1111. DOI: 10.1161/01.ATV.0000163262.83456.6d.
209 - Eiserich JP1, Baldus S, Brennan ML, Ma W, Zhang C, Tousson A, Castro L, Lusis AJ, Nauseef WM, White CR, Freeman BA. Myeloperoxidase, a leukocyte-derived vascular NOoxidase. Science. 2002, 296, 2391–2394. DOI: 10.1126/science.1106830.
210 - La Rocca G, Di Stefano A, Eleuteri E, Anzalone R, Magno F, Corrao S, Loria T, Martorana A, Di Gangi C, Colombo M, Sansone F, Patanè F, Farina F, Rinaldi M, Cappello F, Giannuzzi P, Zummo G. Oxidative stress induces myeloperoxidase expression in endocardial endothelial cells from patients with chronic heart failure. Basic Res Cardiol. 2009;104:301–320. DOI: 10.1007/s00395-008-0761-9.
211 - Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Evaluation of a novel anti-ischemic agent in acute coronary syndromes: design and rationale for the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation acute coronary syndromes (MERLIN)-TIMI 36 trial. Am Heart J. 2006;151:1186.e1–9. DOI: 10.1016/j.ahj.2006.01.004.
212 - Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Münzel T, Simoons ML, Hamm CW; CAPTURE Investigators. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003;108:1440–1445. DOI: 10.1161/01.CIR.0000090690.67322.51.
213 - Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Morgenthaler NG, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B; ProHOSP Study Group. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care. 2010;14:R106. DOI: 10.1186/cc9055.
214 - Kruger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia. Am J Respir Crit Care Med 2010;182:1426–1434. DOI: 10.1164/rccm.201003-0415OC
215 - Choudhary R, Gopal D, Kipper BA, Landa ADLP, Aramin H, Lee E, Shah S, Maisel AS. Cardiorenal biomarkers in acute heart failure. J Ger Cardiol. 2012;9:292−304. DOI: 10.3724/SP.J.1263.2012.02291.
216 - Maisel A, Neath SX, Landsberg J, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Möckel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS, Di Somma S, Anand I, Ng LL, Daniels LB, Christenson RH, Potocki M, McCord J, Terracciano G, Hartmann O, Bergmann A, Morgenthaler NG, Anker SD. Use of Procalcitonin (PCT) for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: Results from the BACH (Biomarkers in Acute Heart Failure) trial. Eur J Heart Fail. 2012;14:278–286. DOI: 10.1093/eurjhf/hfr177.
217 - Herget-Rosenthal S, Marggraf G, Pietruck F, Hüsing J, Strupat M, Philipp T, Kribben A. Procalcitonin for accurate detection of infection in hemodialysis. Nephrol Dial Transplant. 2001;16:975–979. DOI: 10.1093/ndt/16.5.975.
218 - Herget-Rosenthal S, Marggraf G, Hirsch T, Jakob HG, Philipp T, Kribben A. Modulation and source of procalcitonin in reduced renal function and renal replacement therapy. Scand J Immunol. 2005;61:180–186. DOI: 10.1111/j.0300-9475.2005.01545.x.
219 - Yamaguchi T, Baba K, Doi Y, Yano K. Effect of adrenomedullin on aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. Life Sci. 1995;56:379–387. PMID: 7830499 [PubMed—indexed for MEDLINE].
220 - Yandle T, Troughton R. Improving risk stratification in heart failure: a role for new biomarkers? Eur J Heart Fail. 2010;12:315–318. DOI: 10.1093/eurjhf/hfq030.
221 - Nicholls MG1, Charles CJ, Lainchbury JG, Lewis LK, Rademaker MT, Richards AM, Yandle TG. Adrenomedullin and heart failure. Regul Pept. 2003;112:51–60. DOI: 10.1291/hypres.26.S135.
222 - Chan D, NG LL. Biomarkers in acute myocardial infarction. BMC Med 2010; 8: 34. DOI: 10.1186/1741-7015-8-34.
223 - Gaggin HK, Januzzi JL Jr. Biomarkers and diagnostics in heart failure. Biochim Biophys Acta. 2013;1832:2442–2450. DOI: 10.1016/j.bbadis.2012.12.014.
224 - D’Marco L, Bellasi A, Raggi P. Cardiovascular biomarkers in chronic kidney disease: state of current research and clinical applicability. Disease Markers. 2015;ID 586569. DOI: 10.1155/2015/586569.
225 - Junyent M, Martinez M, Borras M, Bertriu A, Coll B, Craver L, Marco MP, Sarró F, Valdivielso JM, Fernández E. Usefulness of imaging techniques and novel biomarkers in the prediction of cardiovascular risk in patients with chronic kidney disease in Spain: the NEFRONA project. Nefrologia 2010;30:119–126. DOI: 10.3265/Nefrologia.pre2010.
226 - Wheeler DC, Townend JN, Landray MJ. Cardiovascular risk factors in predialysis patients: baseline data from the Chronic Renal Impairment in Birmingham (CRIB) study. Kidney Int Suppl 2003; 84:S201–S203.
227 - Takamatsu N, Abe H, Tominaga T, Nakahara K, Ito Y, Okumoto Y, Kim J, Kitakaze M, Doi T. Risk factors for chronic kidney disease in Japan: a community-based study. BMC Nephrol. 2009;10:34. DOI: 10.1186/1471-2369-10-34.
228 - Shan Y, Zhang Q, Liu Z, Hu X, Liu D. Prevalence and risk factors associated with chronic kidney disease in adults over 40 years: a population study from Central China. Nephrology. 2010;15:354–361. DOI: 10.1111/j.1440-1797.2009.01249.x.
229 - Baumeister SE, Boger CA, Kramer BK, Döring A, Eheberg D, Fischer B, John J, Koenig W, Meisinger C. Effect of chronic kidney disease and comorbid conditions on health care costs: a 10-year observational study in a general population. Am J Nephrol. 2010;31:222–229. DOI: 10.1159/000272937.
230 - Bossola M, Tazza L, Merki E, Giungi S, Luciani G, Miller ER, Lin EB, Tortorelli A, Tsimikas S: Oxidized low-density lipoprotein biomarkers in patients with end-stage renal failure: acute effects of hemodialysis. Blood Purif. 2007;25:457–465. DOI:10.1159/000112465.
231 - Sampath P, Achuthan R, Mahdi OG, Nalini S. Oxidized low-density lipoprotein. Methods Mol Biol. 2010;610:403–417. DOI: 10.1007/978-1-60327-029-8_24.
232 - Shoji T, Ishimura E, Inaba M, Tabata T, Nishizawa Y. Atherogenic lipoproteins in end-stage renal disease. Am J Kidney Dis. 2001;38:S30–33. DOI: 10.1053/ajkd.2001.27393.
233 - Witko-Sarsat V, Friedlander M, Nguyen Khoa T, Capeillère-Blandin C, Nguyen AT, Canteloup S, Dayer JM, Jungers P, Drüeke T, Descamps-Latscha B. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol. 1998;161:2524–2532.
234 - Gonzalez E, Bajo MA, Carrero JJ, Lindholm B, Grande C, Sánchez-Villanueva R, Del Peso G, Díaz-Almirón M, Iglesias P, Díez JJ, Selgas R. An increase of plasma advanced oxidation protein products levels is associated with cardiovascular risk in incident peritoneal dialysis patients: a pilot study. Oxid Med Cell Longev. 2015; ID 219569. DOI: 10.1155/2015/219569.
235 - Witko-Sarsat V, Gausson V, Descamps-Latscha B. Are advanced oxidation protein products potential uremic toxins? Kidney Int Suppl. 2003;84:S11–14. DOI: 10.1046/j.1523-1755.63.s84.47.x.
236 - Lefèvre G, Beljean-Leymarie M, Beyerle MF, Bonnefont-Rousselot D, Cristol JP, Thérond P, Torreilles J: Evaluation de la peroxydation lipidique par le dosage des substances réagissant avec l’acide thiobarbiturique. Ann Biol Clin. 1998;56:305–319. PMID: 9754263 [PubMed—indexed for MEDLINE].
237 - Cottone S, Mule` G, Guarneri M, Palermo A, Lorito MC, Riccobene R, Arsena R, Vaccaro F, Vadala` A, Nardi E, Cusimano P, Cerasola G: Endothelin-1 and F2-isoprostane relate to and predict renal dysfunction in hypertensive patients. Nephrol Dial Transplant. 2009;24:497–503. DOI: 10.1093/ndt/gfn489.
238 - Lavi S, Yang EH, Prasad A, Mathew V, Barsness GW, Rihal CS, Lerman LO, Lerman A: The interaction between coronary endothelial dysfunction, local oxidative stress, and endogenous nitric oxide in humans. Hypertension. 2008;51:127–133. DOI: 10.1161/HYPERTENSIONAHA.107.099986.
239 - Giustarini D, Dalle-Donne I, Tsikas D, Rossi R: Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci. 2009;46:241–281. DOI: 10.3109/10408360903142326.
240 - Labio ́ s M, Martinez M, Gabriel F, Guiral V, Dasi F, Beltra ́ n B, and Muñoz A. Superoxide dismutase and catalase anti-oxidant activity in leucocyte lysates from hypertensive patients: effects of eprosartan treatment. J Renin Angiotensin Aldosterone Syst. 2009;10:24–30. DOI: 10.1177/1470320309104067.
241 - Heywood JT: The cardiorenal syndrome: lessons from the ADHERE database and treatment options. Heart Fail Rev. 2004;9:195–201. DOI: 10.1007%2Fs10741-005-6129-4.
242 - Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006;47:76–84. DOI: 10.1016/j.jacc.2005.09.022.
243 - Stevenson LW, Nohria A, Mielniczuk L. Torrent or torment from the tubules? Challenge of the cardiorenal connections. J Am Coll Cardiol. 2005;45:2004–2007. DOI: 10.1016/j.jacc.2005.03.028.
244 - van Kimmenade RR, Januzzi JL Jr., Baggish AL, Lainchbury JG, Bayes-Genis A, Richards AM, Pinto YM. Amino-terminal pro-brain natriuretic Peptide, renal function, and outcomes in acute heart failure: redefining the cardiorenal interaction? J Am Coll Cardiol. 2006;48:1621–1627. DOI: 10.1016/j.jacc.2006.06.056.
245 - Leier CV. Renal roadblock in managing low output heart failure. Crit Care Med. 2004;32:1228-1229. DOI: 10.1097/01.CCM.0000125510.02846.AF.
246 - Shlipak MG. Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med. 2003;138:917–924. DOI: 10.7326/0003-4819-138-11-200306030-00013.