Result of the soil chemical analysis on the 11 locations in the Philippines.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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According to the most recent American College of Cardiology (ACC)/American Heart Association (AHA) reports, 46% of U.S. adults now develop hypertension and take antihypertensive drugs in their lifetime [1, 2]. Prevention and treatment of hypertension and its target organ complications cost several hundreds of billion dollars a year to the U.S. economy [3, 4, 5, 6]. Although the causes of hypertension are multifactorial, the activation of circulating (endocrine), tissue (paracrine) and intracellular (intracrine) RAS via angiotensin II (ANG II) remains one of most important contributing mechanisms [1, 2, 3, 4, 5, 6, 7]. Indeed, angiotensin-converting enzyme (ACE) inhibitors, ANG II receptor blockers (ARBs), and renin inhibitors, which block the RAS at the enzymatic or receptor levels, are widely used to treat hypertension, reduce cardiovascular and renal disease risks, and prevent target organ damage [1, 2, 3, 4, 5, 6, 7]. However, clinical trials have shown that not all RAS-targeting drugs have the same efficacy of blocking the actions of ANG II and afford the same degree of cardiovascular, blood pressure and renal protection [1, 2, 3, 4, 5, 6]. Some patients continue to develop cardiovascular and renal complications despite being treated with one or more than two of these blockers [7, 8]. The underlying mechanisms responsible for these clinical observations are not well understood. One of the possibilities may be that not all ARBs have the same ability to enter the cells to block intracellular ANG II. Some, but not all, ARB(s) such as telmisartan and losartan may exert therapeutic effects beyond the classic ARBs’ properties.
There is accumulating evidence that ANG II acts not only as an endocrine or paracrine hormone activating cell surface ANG II receptors, but also as an intracellular or intracrine peptide activating intracellular ANG II receptors, though the precise roles of the latter remain largely unknown [9, 10, 11]. Indeed, in addition to activating cell surface ANG II receptors, circulating and paracrine ANG II can readily enter the cells via AT1 receptor-mediated endocytosis. The ANG II/AT1 receptor complex internalized into endosomes may continue to transmit signals from endosomes or be translocated to the nucleus to induce long-lasting genomic effects [12, 13]. Recently, we and others have used innovative in vitro cell expression system [14, 15, 16], in vivo adenoviral gene transfer of an intracellular ANG II protein selectively in proximal tubule cells of the rat and mouse kidneys [17, 18], or genetically modified mouse models to investigate the physiological roles and mechanisms of actions of intratubular and intracellular ANG II in the proximal tubules of the kidney, with a focus on basal blood pressure homeostasis and ANG II-induced hypertension [19, 20]. Specifically, we have determined whether intracellular ANG II is derived from AT1 (AT1a) receptor-mediated uptake by the proximal tubule cells, and whether proximal tubule-selective expression of an intracellular ANG II fusion protein in the rat and mouse kidney increases the expression and activity of NHE3, promotes proximal tubular sodium and fluid reabsorption, and therefore elevates arterial blood pressure [17, 18, 19, 20, 21, 22, 23]. These new studies have generated new knowledge to improve, and provided new insights into our understanding of renal mechanisms of hypertension involving both endocrine, paracrine and intracellular ANG II, and perhaps aid the development of new classes of multifunctional drugs to treat ANG II-induced hypertension and its target organ damage by blocking not only extracellular but also intracellular and nuclear actions of ANG II. Accordingly, the objectives of this chapter are to critically review, analyze, and discuss the recent developments and progresses in the studies of novel renal mechanisms of hypertension with a focus on the roles of intratubular and intracellular ANG II in the proximal tubules of the kidney.
Angiotensinogen, a ∼60 kDa α2 globulin in the serpin family, is the primary, if not the only, substrate for the RAS super family. It is well-recognized that angiotensinogen is primarily expressed or produced in the liver under physiological conditions. Human angiotensinogen consists of 452 amino acids, whereas rodent’s angiotensinogen may vary in its molecular size slightly from human form [24, 25, 26, 27]. Angiotensinogen, not active in itself, is released from the liver and cleaved in the circulation by the rate-limiting enzyme renin to form the still inactive decapeptide ANG I. This is followed by the conversion of inactive ANG I to the active and potent peptide ANG II, initiating important biological and physiological actions. A second enzyme called angiotensin I-converting enzyme (ACE) acts to convert ANG I to form the biologically active ANG II, initiating an important biochemical and physiological angiotensinogen/renin/ANG I/ACE/ANG II cascade (see below section on ACE). Accordingly, the recognized and primary role of angiotensinogen is to serve as a key substrate to the production of ANG II in the circulation and tissues.
In the kidney, angiotensinogen mRNAs and proteins have been localized in the kidney, primarily in the proximal tubules [28, 29, 30]. Immunohistochemistry, immunoelectron microscopy and non-isotopic hybridization histochemistry have demonstrated the localization of angiotensinogen mRNAs and proteins in the proximal convoluted and straight tubules of the cortex, with glomerular mesangial cells and medullary vascular bundles also being immunopositive in neonatal rat kidney [29, 30]. In the adult rat kidney, however, angiotensinogen mRNA expression was localized primarily in the proximal convoluted tubules, whereas electron-microscopic immunohistochemistry localized angiotensinogen immunostaining in the apical membrane of proximal convoluted tubules [29, 30]. By contrast, few if any angiotensinogen mRNAs and proteins are localized in the glomeruli, mesangial cells, or distal nephrons under physiological conditions [29, 30].
Although most of angiotensinogen in the circulation is derived from the liver, there is evidence showing that angiotensinogen is also expressed and produced in the kidney [28, 31, 32, 33]. Kobori et al. have consistently shown that angiotensinogen mRNA expression and proteins are increased in the proximal tubules of the kidney in ANG II-infused rats [28, 31, 32, 33]. However, Matsusaka et al. have demonstrated that there were no significant differences in the levels of angiotensinogen and ANG II proteins in the kidney between wildtype mice and mice with kidney-specific angiotensinogen knockout [34]. It was further found that angiotensinogen protein and ANG II levels in the kidney were nearly abolished in mice with liver-specific knockout of angiotensinogen [34]. The studies of Kobori et al. and Matsusaka et al. suggests that liver-derived angiotensinogen is the primary source of renal angiotensinogen protein and ANG II under physiological conditions, but during the ANG II-induced hypertension, angiotensinogen mRNAs and proteins are also expressed in the kidney proximal tubules.
Renin, the rate-limiting enzyme first discovered to increase blood pressure in rabbits by Tigerstedt and Bergman in 1898 [35], is an aspartyl proteinase or angiotensinogenase. Renin plays the most critical role in the initiation of the angiotensinogen/renin/ACE/ANG II/AT1 receptor activation in the cardiovascular, kidney, and other major target tissues. Human renin precursor consists of 406 amino acids with a pre- and a pro-segment of 20 and 46 amino acids, respectively [36]. Mature human renin contains 340 amino acids and a molecular wt. of 37 kDa [36]. Renin, renin activity, and its mRNA have been localized in the kidney, submaxillary glands, blood vessels, heart, adrenal glands, and brain tissues by enzymatic assays, immunohistochemistry, in situ hybridization histochemistry etc. [37, 38, 39]. In the kidney, active renin is primarily localized in the juxtaglomerular apparatus (JGAs) in the afferent arterioles of the kidney under both physiological and diseased conditions [40, 41, 42]. For example, light and electron microscopic immunocytochemistry with an antibody to purified human renal renin localized renin in the secretion granules of the epithelioid cells of the afferent arteriole of the JGAs, in renal artery stenosis, or in Bartter’s syndrome [36, 37]. In the dog kidney, we have used an in vitro autoradiographic approach to localize active renin using radiolabeled renin inhibitors [40, 41, 42]. High resolution light microscopic autoradiography specifically localized active renin to the vascular pole of the glomeruli, or the JGAs (Figure 1) [40, 41, 42].
Intrarenal localization of renin in the juxtaglomerular apparatus (A: JGA), angiotensin-converting enzyme (B: ACE), and angiotensin II AT1 receptors in the kidney (C: AT1 or AT1a) using quantitative in vitro autoradiography. C, renal cortex; G, glomerulus; IM, inner medulla; ISOM, inner stripe of the outer medulla; PCT, proximal convoluted tubule.
In the proximal tubule of the kidney, renin mRNAs have been reported [43, 44]. Renin activity and mRNAs were detectable in cultured rabbit proximal tubule cells [45], in isolated proximal convoluted and straight tubules, but not in outer medullary collecting ducts [44]. Tang et al. reported that all major components of the RAS, including angiotensinogen, angiotensin converting enzyme, and renin, were expressed in an immortalized rat proximal tubule cell line [45]. However, there is also evidence that renin localized in the proximal tubules may be due to the uptake of circulating renin after filtration [46, 47]. Taugner et al. demonstrated that the reabsorptive pinocytosis of the filtered renin was the primary source of tubular renin in the kidney [46], whereas Iwao et al. used light and electron microscopic autoradiography to localize 125I-labeled renin accumulated in the apical membranes of the proximal convoluted tubules [47]. Taken together, these studies strongly support the concept that in addition to local biosynthesis and expression, circulating or interstitial renin may be taken up by the proximal convoluted tubules in the kidney.
The 2nd key enzyme for the activation of the RAS is ACE, a dipeptidyl carboxypeptidase I, kininase II and EC 3.4.15.1 [48]. Corvol’s group first molecularly cloned ACE from human vascular endothelial cells [48], whereas Bernstein’s group cloned ACE from the mouse kidney in 1988, respectively [49]. ACE in humans consists of 1306 residues with a signal peptide of 29 amino acids [48], whereas ACE in mice contains 1278 amino acids [49]. Approximately 80% of the amino acid sequences are similar between human and mouse ACE. There are two ACE isozymes, one somatic isozyme in the lung, vascular endothelial cells, renal epithelial cells, and testicular Leydig cells, and the other germinal isoenzyme solely in sperm [50, 51, 52]. The key actions of ACE are to convert the biologically inactive ANG I to the active peptide ANG II, and to degrade the vasoactive peptide bradykinin. Thus, ACE is most critical for the generation of ANG II in the circulation and tissues.
Abundant ACE is expressed and localized in the kidney, especially in the proximal tubules and glomerular and vascular endothelial cells of intrarenal blood vessels [53, 54, 55, 56, 57]. We and others have localized ACE proteins and its mRNA expression in the kidney using quantitative in vitro autoradiography, immunohistochemistry, and in situ hybridization histochemistry (Figure 1). For example, the Mendelsohn’s group first localized ACE in the rat kidney using quantitative in vitro autoradiography with the radiolabeled ACE inhibitor lisinopril, 125I-351A [53]. ACE was localized primarily to the inner cortex, corresponding to the proximal tubules and blood vessels [53]. We found that infusion of ANG II for 2 weeks significantly increased, rather than downregulated, ACE in the proximal tubules of the rat kidney [54]. At higher resolutions, Brunevaly et al. and others showed ACE primarily in the microvilli and brush borders of the proximal tubules in the human kidney [55, 56, 57]. In the vasculature, ACE was localized to the vascular endothelial cells especially in the peritubular capillaries, but not glomerular capillaries of the kidney [53, 54, 55, 56, 57]. ACE was also localized inside the renal vascular endothelial and proximal tubular cell in endoplasmic reticulum, endosomes, and nuclear envelope, suggesting the presence of intracellular and/or nuclear ACE [53, 54, 55, 56, 57]. However, only very low levels of ACE were detected in the inner medulla.
Angiotensin II (ANG II) is undoubtedly the most powerful peptide in the RAS super family, playing a key role in regulating renal blood flow, glomerular filtration, and proximal tubular reabsorption of sodium and fluid, contributing to normal blood pressure and body salt and fluid homeostasis [58, 59, 60, 61, 62, 63, 64]. It is well-recognized that the levels of ANG II in the kidney, especially in the proximal tubules, are higher than in the plasma or other tissues. Indeed, local expression and biosynthesis of angiotensinogen, renin, and ACE in the proximal tubules of the kidney significantly contribute to high levels of ANG II levels in the kidneys under physiological conditions [64, 65, 66, 67, 68]. Furthermore, ANG II levels are further increased in the kidney of animal models of ANG II-dependent hypertension, even though the circulating and JGA renin and ACE are suppressed [67, 68, 69, 70, 71, 72, 73]. This is likely due to the fact that the proximal tubules express all major components of the RAS necessary for the formation of ANG II [38, 47, 54, 59, 67, 74, 75], the proximal tubules have a greater capacity to take up circulating ANG II via AT1 (AT1a) receptor-mediated mechanisms [14, 19, 20, 67], and to augmentation of the expression or generation of angiotensinogen, ACE and ANG II in ANG II-induced hypertension [54, 67, 70, 73]. Finally, ANG II is not only generated in the intratubular fluid compartment, but also localized in intracellular organelles, such as endosomes, mitochondria, and nuclei [15, 67, 71, 74, 75], where it serves as an important intracellular or intracrine peptide.
It is now well-accepted that ANG II binds to and activates two different classes of G protein-coupled receptors (GPCRs) to induce well-recognized cardiovascular, renal and blood pressure responses, following the successful development of nonpeptide ANG II type 1 and type 2 receptor antagonists [76, 77, 78]. Molecular cloning of AT1 and AT2 receptors and studies of animal models with genetically knockout of these receptors further confirms their pharmacological characterization. Murphy et al. [79] and Sasaki et al. [80] successfully cloned the AT1 receptor in 1991, showing that the AT1 receptor shares the seven-transmembrane-region motif of the GPCR superfamily. AT1 receptors mediate the well-known actions of ANG II on vasoconstriction, cardiac hypertrophy, hypertensive, renal salt retention, as well as aldosterone biosynthesis [76, 77, 78, 81]. The AT2 receptor was cloned by Mukoyama et al. [82], Nakajima et al. [83], and Kambayashi et al. [84], respectively. The AT2 receptor was found to have 34% of the identical sequence to the AT1 receptor, sharing a seven-transmembrane domain topology of GPCRs [82, 83, 84]. However, the roles and signal transduction pathways for the AT2 receptor remain incompletely understood.
In the kidney, the AT1 receptor is widely expressed and localized in different structures or cell types, most prominent in three anatomical regions, that is, the glomerulus, proximal tubules, and the inner stripe of the outer medulla, corresponding the vasa recta blood vessels and renomedullary interstitial cells (Figure 1) [85, 86, 87]. We and others have consistently localized the AT1 receptor in the rodent and human kidneys using quantitative in vitro and in vivo autoradiography, with high levels of these receptors in the glomerulus, proximal tubules, and renomedullary interstitial cells (Figure 1) [85, 86, 87]. Other anatomical regions or renal structures may express low levels of AT1 receptor expression, detectable with RT-PCR or immunohistochemistry. AT1 receptors have also been localized in intracellular organelles, for example, endosomes, mitochondria, and nuclei in the proximal tubule cells, suggesting an important intracellular roles [67, 74, 88, 89, 90]. By contrast, the levels of AT2 receptor expression in the kidney are species-related or closely associated with the kidney development. Indeed, high levels of AT2 receptors are expressed extensively in the developing fetal and neonatal tissues, but most of them disappear before reaching the adulthood [87]. Nevertheless, the expression of AT2 receptors appears to persist in the adrenal medulla, proximal tubules, and the adventitia of human kidney blood vessels, suggesting potential roles for these receptors in these target tissues [85, 86, 87, 91, 92, 93].
In contrast to the classic dogma that ANG II only binds to and activates cell surface GPCRs to initiate downstream signaling responses, ANG II can also bind and activate intracellular GPCRs to induce long-term genomic effects. The RAS includes an extracellular system and an intracellular system. ANG II acts as the principle effector of both extracellular and intracellular RAS. Extracellular ANG II includes circulating (endocrine) and paracrine ANG II, which plays the classical roles of the RAS through activation of cell surface GPCRs [76, 77, 78, 81, 94, 95]. Intracellular ANG II includes intracellularly formed ANG II (intracrine) and ANG II internalized through AT1 (AT1a) receptor-mediated endocytosis [96, 97, 98, 99, 100, 101]. The roles of circulating and paracrine ANG II and its GPCR-mediated signaling mechanisms via cell surface receptors have been extensively investigated. By contrast, the roles of intracellular ANG II and its mechanisms of actions remain poorly understood. This disparity in our understanding extracellular versus intracellular ANG II has led many to assume that ANG II only activates cell surface receptors to induce all of its biological and physiological responses, and that all ARBs would only block cell surface receptors to produce the same beneficial effects. Thus, an intracellular ANG II system is thought to be unnecessary in the regulation of cardiovascular, blood pressure, and renal physiology and diseases.
However, recent studies strongly suggest that these views may be revised for a number of reasons [96, 97, 98, 99, 100, 101]. First, it is well-recognized that extracellular ANG II is continuously internalized with its receptors after it activates cell surface receptors. This has long been interpreted only as required for the desensitization of cell surface receptors to repetitive stimulation by extracellular ANG II by moving the ANG II/AT1 complex into the lysosomal pathway for degradation. There is evidence, however, that the activated agonist/receptor complex internalized into the endosomes may continue to transmit ras/mitogen-activated protein kinase (MAPK) signaling [12, 13]. Ras and MAPK signaling for AT1a, vasopressin V2, and β2 adrenergic receptors (β2AR) have been reported in endosomal membranes [12, 13, 15, 16], the endoplasmic reticulum, the Golgi or the nucleus independent of cell surface receptor-initiated signaling [81, 88, 89, 102]. Second, ANG II exerts long-lasting genomic or transcriptional effects, which may be independent from the well-recognized effects induced by activation of cell surface receptors [97, 98, 99, 102, 103]. ANG II induces the expression or transcription of many growth factors and proliferative cytokines including nuclear factor-κB (NF-κB) [104, 105, 106, 107], monocyte chemoattractant protein-1 (MCP-1) [106, 108], TNF-α [107], and TGF-β1 [102, 109, 110]. While hemodynamic responses to ANG II often occur in seconds or minutes, cellular growth, mitogenic, proliferative and fibrotic responses to ANG II may last from hours to weeks and months. Since the cell surface AT1 (AT1a) receptors may be desensitized in response to sustained exposure to endocrine and paracrine ANG II, the long-term genomic effects of ANG II, as observed in cardiovascular, hypertensive, and renal diseases, are at least in part mediated by intracellular ANG II system. Third, not all ARBs, ACE or renin inhibitors are created equal to block both extracellular and intracellular ANG II systems. ARBs may differ in their lipophilic ability to enter the cells to block intracellular AT1 receptors [111, 112, 113]. Indeed, ARBs show different effects on uric acid metabolism, cell proliferation, oxidative stress, nitric oxide production and PPAR-γ activity [111, 112, 113]. We and others have shown that losartan internalized with AT1a and AT1b receptors, albeit at a slower rate than ANG II [19, 20, 67, 103, 114], and to attenuate ANG II-induced intracellular and nuclear effects [15, 88, 89, 102, 103]. Moreover, telmisartan not only blocks AT1 receptors, but also acts as a partial activator of liver-specific peroxisome proliferator-activated receptor γ (PPAR-γ) [111, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157]. Finally, some clinical studies have shown that even treated with renin inhibitors, ACE inhibitors or ARBs, there are some patients who still progress to hypertension and suffer from cardiovascular and renal complications [111, 115, 116, 117]. These data suggest that additional mechanisms should be involved and studied accordingly. Thus, the new challenges to the field are to study whether and how intracellular ANG II may contribute to these mechanisms and design multifunctional drugs to block both extracellular and intracellular ANG II-induced effects.
We and others have investigated whether circulating and local paracrine ANG II is taken up by the proximal tubules of the kidney via AT1 (AT1a) receptor-mediated endocytosis [19, 20, 118, 119, 120, 121], and whether internalized ANG II and AT1a receptors are co-localized in the endosomal compartment and nucleus (Figure 2) [67, 74, 88, 89]. Our studies demonstrated that global deletion of AT1a receptors blocked the uptake of unlabeled Val5-ANG II [19] or [125I]Val5-ANG II in the kidney of AT1a-KO mice [20]. However, these studies focused only on the entire kidney, and what nephron segments involved in taking up unlabeled Val5-ANG II or [125I]Val5-ANG II could not be determined using these approaches [19, 20]. We further used cultured proximal tubules cells to test whether proximal tubule cells take up extracellular ANG II and the mechanisms involved (Figure 2) [14, 100, 122, 123, 124, 125, 126]. The advantages of using these cells for the proposed studies are that ANG II receptors are abundantly expressed and localized in both apical (AP) and basolateral (BL) membranes [127, 128, 129, 130, 131]. However, it has not been determined whether ANG II receptors in AP or BL membranes mediate ANG II uptake in the proximal tubules. In a previous study using a porcine proximal tubule cell line expressing a rabbit AT1 receptor, AT1-mediated uptake of [125I]-ANG II was found to be significantly different between AP and BL membranes [130]. AT1-mediated uptake of [125I]-ANG II was more robust and efficient in AP membranes than in BL membranes [130]. Conversely, ANG II-induced AT1 receptor internalization was reportedly much faster in BL membranes than in AP membranes of OK cells [131]. Thus these differences inAT1-mediated uptake of [125I]-ANG II or ANG II-induced AT1 receptor endocytosis or internalization may underscore the differences in the cell types used or experimental conditions.
All major components of the circulating RAS, including angiotensinogen (AGT), renin, angiotensin I (ANG I), and ANG II, may be filtered by the kidney glomerulus and taken up by the proximal tubules. Alternatively, all major components of the RAS may be expressed and localized in the proximal tubules of the kidney. ACE, angiotensin-converting enzyme and APA, aminopeptidase A.
In addition to AT1 (AT1a) receptors, other factors may also regulate the uptake of extracellular ANG II by proximal tubule cells. AP membranes of proximal tubule cells express abundant endocytic receptor megalin, which plays a crucial role in mediating the uptake of low molecular weight (LMW) proteins in proximal tubule cells [132, 133, 134, 135, 136]. Deletion of megalin in mice led to the development of LMW proteinuria [135]. Interestingly, megalin also binds and internalizes ANG II in immortalized yolk sac cells (BN-16 cells) [136]. We have demonstrated that siRNA knockdown of megalin expression or caveolin 1 in proximal tubule cells significantly attenuated ANG II uptake by proximal tubule cells [122, 123]. However, the extent to which megalin- and caveolin 1-mediate ANG II uptake in proximal tubule cells is significantly smaller than that mediated by AT1 (AT1a) receptor-dependent mechanism [19, 20, 122, 123].
We have mechanistically investigated that AT1 (AT1a) receptor-mediate the uptake of extracellular ANG II by proximal tubule cells in vitro and circulating ANG II in vivo [19, 20, 122, 123, 124, 125, 126]. It has been previously shown that in vascular smooth muscle cells (VSMCs), cardiomyocytes, and COS-7 cells, β2 adrenergic receptors, AT1a, epidermal growth factor receptors, and insulin receptors are internalized via the canonical clathrin-dependent pathway [137, 138, 139, 140, 141, 142, 143, 144]. Clathrin-coated pits play an important role in invaginating and pinching off the plasma membranes to form coated vesicles and targeted to endosomes [138, 140, 142]. GPCR kinases (GRKs), small GTP-binding proteins, such as Rab5, and β-arrestins are reportedly involved in clathrin-dependent AT1a endocytosis [145, 146]. However, dominant-negatives, siRNAs or knockout targeting dynamin, GRKs or β-arrestins have little effects on AT1a receptor endocytosis in some studies, suggesting that alternative (non-canonical) pathways may also be involved in AT1a receptor endocytosis [137, 138, 139, 140, 141, 142, 143, 144, 145, 146].
There is evidence to suggest that tyrosine phosphatases may be involved in ANG II-induced AT1 receptor endocytosis in AP and BL membranes, since the endocytic response was inhibited by the tyrosine phosphatases inhibitor, phenylarsine oxide (PAO), rather than by pertussis toxin [147, 148, 149, 150, 151]. Colchicine, an inhibitor of cytoskeleton microtubules [148], also appeared to inhibit AT1 receptor-mediated ANG II uptake and its effects in rat proximal tubule cells [150, 151]. The role of clathrin-coated pits in mediating AT1 receptor-mediated ANG II uptake was also investigated, but we found that deletion of clathrin-coated pits with sucrose or specific siRNAs to knock down clathrin light (LC) or high chain subunits (HC) failed to alter AT1-mediated uptake of Val5-ANG II [151]. However, AT1-mediated uptake of Val5-ANG II was significantly inhibited by colchicine or siRNA knocking down of microtubule-associated proteins, MAP-1A or MAP-1B, in proximal tubule cells [151]. Our studies therefore support the scientific premise that the noncanonical microtubule-dependent endocytic pathway may be involved in mediating the AT1-mediated uptake of ANG II in proximal tubule cells.
How ANG II and AT1 receptors are internalized into the endosomal compartments and transported to other organelles or the nucleus in proximal tubule cells remains incompletely understood. Intravenous infusion of 125I-labeled ANG II was previously detected in the nuclei of rat vascular smooth muscle cells (VSMCs) and cardiac myocytes [152] or the Golgi of adrenal cells [153]. Cook et al. showed that ANG II and its AT1a receptor were translocated to the nuclei of hepatocytes and VSMCs [154]. In AT1a receptor-expressing HEK 293 cells, internalized AT1a receptors were detected in perinuclear areas as well as in the nuclei [155, 156]. In supporting the above-mentioned studies, we also reported high levels of internalized FITC-labeled ANG II in perinuclear areas and the nucleus, which was inhibited by colchicine and siRNA knockdown of MAP-1A [14, 122, 123, 151]. Taken together, our results strongly suggest that the microtubule-dependent pathway may play an important role in mediating the nuclear translocation of internalized ANG II/AT1 receptor complex in proximal tubule cells. Indeed, a nuclear localization sequence (NLS, KKFKKY, aa307-312) has been identified within the AT1a receptor, which may mediate nuclear trafficking and activation of AT1a receptors by ANG II [155, 156].
In the proximal tubules of the kidney, extracellular ANG II has been reported to stimulate the expression of Na+/H+ exchanger 3 (NHE3) [14, 16, 102, 125], AP insertion of NHE3 [157], Na+/H+ exchanger activity [158, 159, 160, 161], or NHE3-induced 22Na+ uptake in cultured or isolated proximal tubule cells [162, 163]. The signaling mechanisms by which extracellular ANG II increases the expression and activity of NHE3 in proximal tubule cells have been well studied and documented [164, 165, 166, 167, 168, 169]. The most well-described signal mechanism is that ANG II activates cell surface receptor-coupled G proteins, with subsequent increases in IP3 and [Ca2+]i, generation of DG, and activation of PKC [164, 165, 166, 167, 168, 169]. The other well-recognized downstream signaling pathways for extracellular ANG II to induce biological or physiological responses also include activation or inhibition of calcium-dependent calcineurin [170], cAMP-dependent protein kinase A (PKA) [169, 171], Ca2+-independent PLA2 [172], PI 3-kinase [157], c-Src/MAP kinases ERK 1/2 [165], or nuclear factor-κB [173].
According to the principles of the G protein-coupled receptor pharmacology, ANG II must bind to its cell surface receptors to activate intracellular signaling mechanisms in order to induce responses [76, 77, 78, 138]. Upon internalization, however, ANG II may act as an intracellular peptide to induce biological or physiological responses. Indeed, blockade of the endocytosis of AT1 receptors is associated with inhibition of PKC, IP3 formation, and Na+ flux in proximal tubule cells [14, 16, 122, 123, 124, 125, 126, 149, 150]. Furthermore, ANG II-induced AT1 receptor endocytosis is also associated with activation of PLA2 [147, 172], inhibition of adenylyl cyclase [151, 169, 171], and increases in Na+ uptake from AP membranes [149, 150, 151]. We have recently shown that AT1-mediated uptake of extracellular Val5-ANG II was indeed associated with inhibition of basal and forskolin-stimulated cAMP accumulation [125, 151], ANG II-stimulated NHE3 expression [14, 16, 122, 123], and ANG II-induced activation of MAP Kinases ERK1/2 and nuclear factor-κB in proximal tubule cells [14, 16, 124, 126, 151].
Nevertheless, these approaches are unlikely able to distinguish the effects of ANG II mediated by cell surface or intracellular receptors. Previous studies have shown that single cell microinjection or microdialysis of ANG II directly into the cells may distinguish between the effects induced by extracellular ANG II from those induced by intracellular ANG II [15, 102, 174, 175, 176, 177]. Indeed, we have demonstrated that intracellular microinjection of ANG II directly into single rabbit proximal tubule cells induced intracellular [Ca2+]i responses (Figure 3) [10, 15, 16, 81, 177]. We further reported that microinjection of the AT1 blocker losartan abolished the [Ca2+]i response induced by microinjected ANG II, but it only partially blocked the effects of extracellular ANG II [15]. In further proof-of-the concept studies, we showed that ANG II stimulated nuclear AT1a receptors to increase in vitro transcription of mRNAs for TGF1, MCP-1 and NHE3 in isolated rat renal cortical nuclei [102]. These studies provide evidence that intracellular ANG II may activate cytoplasmic and nuclear AT1 receptor to induce important genomic effects in proximal tubule cells [15, 102, 174, 175, 176, 177].
Intracellular microinjection of angiotensin II induces intracellular calcium mobilization in cultured rabbit proximal tubule cells. Adapted from Zhuo et al. with permission [15].
Whether intracellular ANG II may alter biological responses in a cell culture model has been determined by directly expressing an intracellular ANG II fusion protein [9, 11, 15, 88, 89, 90, 102]. Cook et al. overexpressed a cyan fluorescent, intracellular ANG II construct (ECFP/ANG II) with or without a rat yellow fluorescent AT1a receptor (AT1R/EYFP) in rat VSMCs or hepatocytes [9, 97, 98]. They demonstrated that intracellular ANG II induced the proliferation of VSMC via activation of cAMP response element-binding protein (CREB), p38 MAP kinase, and MAP kinases ERK 1/2 [9, 97, 98]. In another study, an intracellular ANG II (pcDNA/TO-iAng II) was expressed in CHO cells to induce cell proliferation, but none of ARBs was found to attenuate the effect of intracellular ANG II on cell proliferation [178, 179]. Nevertheless, these early proof of concept studies suggest that in vitro or in vivo expression of a cyan fluorescent intracellular ANG II fusion protein (ECFP/ANG II) in the proximal tubule cells of wild-type and AT1a-KO mice may be an innovative approach to distinguish the effects of intracellular versus extracellular ANG II.
The physiological roles of intracellular ANG II in the regulation of proximal tubule Na+ reabsorption and normal blood pressure homeostasis remain to be determined. Whether intracellular and/or internalized ANG II may physiologically regulate proximal tubule Na+ transport and blood pressure has not been studied until recently. Indeed, this line of research has been long stymied due to the lack of suitable animal models that express an intracellular ANG II protein, which is not secreted outside the cells and only acts intracellularly. Dr. Reudelhuber’s group was the first to generate genetically modified mouse model that expresses an ANG II-producing fusion protein in the cardiomyocytes of the rat heart [180, 181]. They used the α myosin heavy chain promoter to control the expression of ANG II-releasing fusion protein in the cardiomyocytes. Cardiac specific expression of this ANG II fusion protein led to 10-fold increases in ANG II levels in the heart of these transgenic mice, but it did not elevate ANG II levels in the plasma [180, 181]. This approach is very unique to construct this cardiac-specific ANG II fusion protein with a signal peptide sequence derived from human prorenin and a furin cleavage site. Thus, the expressed ANG II fusion protein will be cleaved by furin, and released into the secretory pathway and the cardiac interstitium [180, 181]. It is expected that this cardiac-specific ANG II fusion protein activates cell surface, but not intracellular receptors. In a different study, Baker et al. expressed an intracellular ANG II peptide in the mouse cardiomyocytes using an adenoviral vector [178]. Cardiac-specific expression of this intracellular ANG II peptide in mice induced cardiac hypertrophy, but not altered blood pressure and plasma ANG II [99, 178]. Furthermore, the AT1 receptor blocker failed to block the cardiac hypertrophic effect of this peptide, suggesting that AT1 receptor may not be involved [99, 178].
In the kidney, a proximal tubule cell-specific promoter may be an ideal approach to express an intracellular ANG II protein selectively in the proximal tubules. For example, the kidney androgen-regulated protein gene (KAP) has been used to drive “proximal tubule-specific” expression of human angiotensinogen and renin in the kidney [182, 183]. It has been shown that the KAP gene is widely expressed in the kidney, with its expression reportedly confined to the proximal tubules and regulated by androgen and estrogen [184, 185]. The advantages of this approach are its usefulness for studying the sexual dimorphic regulation of angiotensinogen expression in the proximal tubules of the kidney [182, 183].
We have collaborated with Dr. Julie Cook of Ochsner Clinic and Dr. Isabelle Rubera of University of Nice-Sophia, France to develop an adenoviral construct (Ad-sglt2-ECFP/ANG II), which encodes a cyan fluorescent intracellular ANG II fusion protein (ECFP/ANG II) [17, 18]. The sodium and glucose cotransporter 2 promoter, sglt2, was used to drive the expression of ECFP/ANG II selectively in the proximal tubule cells of the rat and mouse kidneys. Sglt2 is expressed almost exclusively in S1 and S2 segments of the kidney proximal tubules [186]. Using this approach, we have determined whether intrarenal adenovirus-mediated expression of intracellular ECFP/ANG II selectively in the proximal tubules of the rat and mouse kidneys increases the expression and activity of NHE3, stimulate proximal tubule sodium reabsorption, and increase blood pressure in rats and mice. We demonstrated that expression of intracellular ECFP/ANG II selectively in the proximal tubules of rats and mice significantly increased NHE3 expression, proximal tubule sodium reabsorption, and blood pressure (Figure 4) [17, 18]. We further showed that AT1 receptor blocker losartan and deletion of AT1a receptors in mice significantly attenuated intracellular ANG II-induced NHE3 expression, proximal tubule sodium reabsorption, and blood pressure responses, suggesting an AT1 (AT1a) receptor-mediated mechanisms.
Overexpression of an intracellular ECFP/ANG II fusion protein selectively in the proximal tubule of the kidney in C57BL/6J or AT1a-KO mice. ECFP/ANG II increased systolic blood pressure and had a significant antinatriuretic response in C57BL/6J but not in AT1a-KO mice. Green blue represents ECFP/ANG II expression in the proximal tubules, whereas Red represents DAPI-stained nuclei in the cortex after conversion from blue color. G, glomerulus. PT, proximal tubule. **p < 0.01 versus control, whereas ++p < 0.01 versus C57BL/6J mice. Reproduced from Zhuo et al. with permission [15].
The Na+/H+ exchanger 3 (NHE3) is the most important Na+ transporter in AP membranes of the proximal tubules of the kidney [187, 188, 189, 190]. NHE3 is directly and indirectly responsible for reabsorbing approximately 50–60% of filtered load of NaCl and 70–80% of filtered load of bicarbonate (HCO3−) [187, 188, 189, 190]. Indeed, nearly all of the measured Na+/H+ exchanger activity in AP membrane vesicles of proximal tubules are mediated by NHE3 [187, 188, 189, 190]. The importance of proximal tubule NHE3 in maintaining body salt and fluid balance and blood pressure homeostasis has not been well studied until recently. Overall, global deletion of the NHE3 gene in all tissues of mice (Nhe3−/−) leads to ∼50% decreases in fluid, Na+ and HCO3− absorption in proximal convoluted tubules, causes salt wasting from the digestive system, and significantly decreases basal blood pressure [191, 192, 193, 194]. One of striking phenotypes is absorptive defects in the small intestines due to intestinal NHE3 deletion [191, 192, 193, 194]. Moreover, the transgenic rescue of the NHE3 transgene in small intestines in Nhe3−/− mice, tgNhe3−/−, failed to rescue the structural and absorptive defects of global NHE3 deletion, with basal blood pressure being similar to those of Nhe3−/− mice [195, 196]. These abnormal phenotypes have been confirmed by us recently [21, 22, 23].
However, these studies using either Nhe3−/− or tgNhe3−/− mice are unable to determine the roles of NHE3 in the proximal tubules of the kidney, since NHE3 is abundantly expressed not only in the proximal tubules of the kidney, but also in small intestines of the gut. To overcome this limitation, we have generated mutant mice with deletion of NHE3 selectively in the proximal tubules of the kidney, PT-Nhe3−/−, using the state of the art Sglt2-Cre/LoxP approach [23]. We directly tested the hypothesis that deletion of NHE3 selectively in the proximal tubules of the kidney would lower basal blood pressure by inhibiting proximal tubule Na+ reabsorption and increasing the pressure natriuresis response in mice [23]. We demonstrated that under basal conditions, PT-Nhe3−/− mice had significantly lower systolic, diastolic, and mean arterial blood pressure than WT mice, accompanied by significantly greater diuretic and natriuretic responses than WT mice, without altering 24 h fecal Na+ excretion, plasma pH, Na+, and bicarbonate levels. Furthermore, we demonstrated that the pressure-natriuresis response, as well natriuretic responses to acute volume expansion and a high salt diet, were significantly augmented in PT-Nhe3−/− mice [23]. Thus, our data support the scientific premise and physiological relevance that NHE3 in the proximal tubules plays an important role in maintaining basal blood pressure homeostasis, and genetic deletion of NHE3 selectively in the proximal tubules of the kidney lowers blood pressure by increasing the pressure-natriuretic response.
Recently, we further investigated whether NHE3 in small intestines and proximal tubules of the kidney plays a key role in ANG II-induced hypertension using Nhe3−/−, tgNhe3−/−, and PT-Nhe3−/− mice [21, 22]. As expected, infusion of a pressor dose of ANG II, 1.5 mg/kg/day, i.p., via an osmotic minipump for 2 weeks markedly increased blood pressure and caused hypertension in C57BL/6J mice (Figure 5) [21, 22]. These hypertensive responses were significantly attenuated in conscious and anesthetized Nhe3−/−, tgNhe3−/−, and PT-Nhe3−/− mice [21, 22, 197]. These results strongly support an important role of NHE3 not only in small intestines, but also in the proximal tubules of the kidney in maintaining basal blood pressure homeostasis and in the development of ANG II-induced hypertension.
Global (Nhe3−/−) or “kidney-selective” deletion of the Na+/H+ exchanger 3 (NHE3) (tgNhe3−/−) in mice significantly attenuates systolic blood pressure response to angiotensin II infusion for 2 weeks (ANG II), 1.5 mg/kg/day, i.p. **p < 0.01 versus their control or basal; ++p < 0.01 versus wildtype; ##p < 0.01 versus ANG II.
Taken together, there is accumulating evidence to support the existence of the circulating (endocrine), local intratubular (paracrine), and intracellular RAS system in the kidney, especially in the proximal tubules. All major components of the RAS, including the substrate angiotensinogen, renin, ACE, ANG II, AT1 and AT2 receptors, have been localized in the circulation, the kidney, and in the proximal tubule. The roles of the circulating and intratubular RAS in the cardiovascular and kidney, and blood pressure regulation have been extensively studied using molecular, cellular, genetic and pharmacological approaches. It is now well-understood that AGT, prorenin, renin, ACE, ANG II and AT1 and AT2 receptors are not only expressed and localized in the proximal tubules under physiological conditions, but the levels of intratubular angiotensinogen, renin, ACE, and ANG II proteins are also significantly increased in the kidney in response to ANG II infusion in spite of suppression of the circulating RAS. Furthermore, there is also increasing evidence supporting the genomic roles of intracellular and nuclear ANG II in the regulation of proximal tubule reabsorption, blood pressure and the development of hypertension. Future studies should focus more on the long-term genomic and hypertensive roles of intracellular, mitochondrial and nuclear ANG II and the underlying signaling mechanisms in ANG II-dependent hypertension and target organ injury.
This work was supported in part by NIH grants, 2R01DK102429-03A1, 2R01DK067299-10A1, and 1R56HL130988-01 to Dr. Zhuo. Ana Paula de Oliveira Leite was supported by scholarships from the Ministry of Education, Brazilian Federal Agency for Support and Evaluation of Graduate Education—CAPES, and Hospital do Rim, Sao Paulo, Brazil, respectively. Drs. Chunling Zhao, Xiaowen Zheng, Jianfeng Zhang were visiting scholars from the Department of Emergency Medicine, The 2nd Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
The authors declare no conflict of interest.
Soybean (Glycine max [L.]) is a leguminous plant that can form a symbiotic relationship with the nitrogen-fixing group of bacteria living in the rhizosphere, which are generally termed as rhizobia. In the Philippines, soybean production has been limited by the poor grain yield which leads to the importation of more than 90% of the country’s demand. Thus, it is essential to look for an alternative way to increase the volume of production per unit area.
The research about tropical bradyrhizobia indicated a high diversity of species and their distribution has been reported to be due to several abiotic and biotic factors such as soil acidity [1, 2, 3], alkalinity [3, 4], temperature [1, 5, 6, 7, 8, 9, 10, 11], climate [12, 13], soil water status [14, 15], soil type [2, 14, 16, 17, 18], and soil management or cultural practices [2, 14, 19, 20, 21, 22]. In case of the Philippines, the pioneer research that was able to identify the most dominant species of bradyrhizobia in the country reported that B. elkanii species was the most abundant, followed by the B. diazoefficiens, B. japonicum, and some yet unclassified Bradyrhizobium sp. [14]. In this later study, it was identified that the distribution of these indigenous species of bradyrhizobia were influenced mainly by the water status of the soil, followed by soil pH, nutrient content, and soil type.
Previous studies have reported that aside from the various agro-environmental factors, the competition with the native rhizobia is a hindrance for a successful inoculation [23, 24]. The utilization of inoculants for legumes had shown promising results for the increase in grain yield as evidenced by recent reports [25, 26]. The role of the biological nitrogen fixation (BNF) in providing the N requirement of the plant in a natural way has been deemed necessary especially these times that the soil has become more degraded due to over-fertilization. The indiscriminate use of NPK fertilizer could cause soil pollution and less crop production [27]. Therefore, it is essential to select and evaluate the symbiotic competitiveness of the indigenous strains which are native and existing in high density in the country. The use of different genetic markers to accurately identify the rhizobia for taxonomic purposes has been proposed [28] and so we have used three genetic markers such as the 16S rRNA gene, 16S-23S rRNA gene internal transcribed spacer (ITS) region, and the rpoB housekeeping gene.
Thus, this study was formulated with the aim to utilize the recently identified indigenous bradyrhizobia in the Philippines and characterize their symbiotic performance with the local soybean cultivars.
The soil samples were collected from 11 locations in the Philippines, where some basic information on the sites are listed in Table 1. The collection of soil was conducted by first removing the surface litters then, obtaining a bar of soil with a dimension of approximately 20 cm in depth and 3 cm in thickness that weighs about 1 kg. A total of 10 subsamples per location were obtained and were mixed thoroughly until a 1 kg of composite soil sample was taken. A 0.5 kg soil was air-dried for the chemical analyses while the remaining 0.5 kg of the fresh soil was used for the soybean cultivation.
Result of the soil chemical analysis on the 11 locations in the Philippines.
Mason et al., 2018
This study
The cultivation of soybean was performed using a 1-L capacity culture pots (n = 3). Each pot was filled with vermiculite and a N-free solution [29] was added at 40% (vol/vol) water content. The culture pots were sterilized by autoclaving for 20 min at 121°C. Meanwhile, the soybean seeds were surface-sterilized by soaking into a 70% EtOh for 30 s, then by a diluted sodium hypochlorite solution (0.25% available chlorine) for 3 min and followed by washing with sterile distilled water for about 6–8 times. Then, a 2–3 g of soil sample was placed on the vermiculite at a depth of about 2–3 cm, the seeds were sown on the soil and the pot was weighed and recorded. The plants were grown inside a growth chamber for 28 days at 28°C (8 h, night) and 33°C (16 h, day) then were supplied weekly with sterile distilled water until the initial weight of the pot was reached.
After 28 days, approximately 20 random nodules were collected from the roots of each soybean plants and were sterilized with 70% EtOh and sodium hypochlorite solution as previously described [29]. Each nodule was homogenized with sterile distilled water in a microtube and streaked on to a yeast-extract mannitol agar (YMA) plate [30]. The YMA plate was incubated in the dark at 28°C for about 1 week until a single colony was formed. After then, the single colony was streaked on to a YMA plate containing a 0.002% (wt/wt) bromothymol blue (BTB) [31] and was incubated as above. Repeated streaking was done until a pure single colony was obtained which was cultured for about 3–4 days in a HEPES-MES (HM) broth culture [32, 33] at 28°C in a shaker for 120 rpm. After then, the bacteria cells were collected by centrifugation at 9000×g and washed with sterile distilled water. The DNA was extracted by using BL buffer as described [34] from the method reported by Hiraishi et al. [35].
For the amplification of the 16S rRNA gene, the primer set: 16S-F: 5′ AGAG TTTGATCCTGGCTCAG-3′ and 16S-R2: 5′- CGGCTACCTTGTTACGACTT-3′ [36]. The PCR tubes were then placed in the PCR Thermal Cycler (TaKaRa Co. Ltd.) with the following conditions: pre-run at 94°C for 5 min; followed by 30 cycles of denaturation at 94°C for 1 min, annealing at 55°C for 1 min, and extension at 72°C for 1 min. Final extension was set at 72°C for 10 min and indefinite preservation at 4°C.
On the other hand, the PCR amplification of the ITS region was conducted using the following primer set: Bra-ITS-F: 5-GACTGGGGTGAAGTCGTAAC-3′ and Bra-ITS-R1: 5′-ACGTCCTTCATCGCC TC-3′ [6]. The PCR cycle for the ITS region was almost the same with the 16S rRNA gene except for a shorter denaturation and annealing periods which were conducted at 30 s for each step.
For the rpoB gene, simplification was done using the following primer sets: rpoB83F: 5′-CCTSATCGAGGTTCAC AGAAGGC-3′ and rpoB1540R: 5′-AGCTGCGAGGAACCGAAG-3′ [37]. The PCR cycle conditions were as follows: pre-run at 94°C for 5 min; followed by 30 cycles of denaturation at 94°C for 30 s, annealing at 60°C for 1 min, and extension at 72°C for 1 min. Final extension was set at 72°C for 5 min and indefinite preservation at 4°C.
The successfully amplified products were subjected to the RFLP treatment using four restriction enzymes which were HhaI, HaeIII, MspI, and XspI. For the rpoB gene, the enzymes that were used for RFLP are HaeIII, MspI, and AluI. The reference strains that were used in this study are the Bradyrhizobium USDA strains (B. japonicum USDA 4, 6T, 38, 62, 115, 122, 123, 124, 125, 127, 129, 135, B. diazoefficiens USDA 110T, B. elkanii 31, 46, 61, 76T, 94, 130, and B. liaoningense 3622T) which were previously described [38]. This was done in a 10-μL reaction mixture containing a 2.5-μL amplified PCR product and was incubated in a 37°C for 16 h. Afterward, a 3–4% agarose gel was used in a submerged gel electrophoresis for about 60 min, stained with ethidium bromide and the patterns were visualized using a Luminiscent Image Analyzer LAS-4000 (FUJIFILM Tokyo, Japan).
After the amplification and the RFLP treatment of the 16S rRNA gene, a single-strain inoculation test was conducted for all the amplified isolates that shared the same restriction enzymes’ fragment patterns with the USDA Bradyrhizobium reference strains. This was done to confirm the strain’s capability to nodulate soybean and was tested on two local varieties which are the PSB-SY2 and Collection 1 which are both commercially available across the country.
The cultivation of soybean was conducted as described above, but without soil. Each isolate was cultured in a YM broth (YMB) [30] at 28°C for about 1 week on a shaker. After then, the cultures were diluted with sterile distilled water at about 106 cells mL−1 and were inoculated on the cultivated soybean at a rate of 1.0 mL per seed. This was done with three replications. After inoculation, the weight of the pot was recorded and it was placed inside a growth chamber with a condition set to mimic the average temperature in the Philippines at 26°C (8 h, night) and 33°C (16 h, day). The same condition was used for the cultivation of an uninoculated control and a positive control pot that was inoculated with B. diazoefficiens USDA110. The pots were kept inside the growth chamber for 28 days and were supplied weekly with sterile distilled water until the initial weight of each pot was reached.
According to the similarities of the band patterns through the RFLP treatment, a representative of the most abundant isolates was chosen for each location. In total, there were 11 isolates that were selected to confirm the nucleotide sequence of the 16S rRNA gene and the ITS region. The sequence primers that were used were reported previously [22]. From the PCR amplified product, the samples were purified according to the protocol of the manufacturer (Nucleospin® Gel and PCR Clean-up; Macherey-Nagel, Germany). Then, the samples were sent to the company for the sequence analysis (Eurofins Genomics, Tokyo, Japan).
Then, the Basic Local Alignment Search Tool (BLAST) program in DNA Databank of Japan (DDBJ) was used to determine the nucleotide homology of the isolates. Only the sequences with a similarity of at least 99% for the 16S rRNA and 96% for the ITS region with our isolates were retrieved from the BLAST database. The alignment was performed using the ClustalW and Neighbor-Joining [21] method was used to construct the phylogenetic trees. The genetic distances were computed using the Kimura 2-parameter model [39] in the Molecular Evolutionary Genetic Analysis (MEGA v7) software [40]. Subsequently, the phylogenetic trees were bootstrapped with 1000 replications. All the nucleotide sequences determined in this study were deposited in DDBJ at
The soil samples that were used in this study were all slightly to moderately acidic (5.22–6.64) with non-saline condition (0.05–0.20 dS/m), low nutrient status as evidenced by low amounts of NPK and CEC (Table 1). These values are generally typical of agricultural soils that are used for crop production all throughout the year. These results showed that the soils used in this study have low fertility status that indicated the need for soil restoration strategies.
The growth morphologies of the pure single colony for each strain of bradyrhizobia were characterized and listed in Table 2. All the isolates were slow growers which were able to form single colonies measuring about 2 mm between 5 and 7 days upon streaking on YMA plates and incubation in a dark room. Based on the morphology, the isolates were grouped into three. Group I include the isolates IS-2, NE1–6, NR-2, and BO-4 which were translucent and the colonies are circular in shape with slightly convex elevation and an entire margin. When they were manipulated with a needle, the colony was liquid. Group II include the isolates BA-24, SO-1, LT-3, and SK-5 were translucent with circular colonies, convex elevation with entire margin. When manipulated with a needle, the colonies have mucoid viscosity. On the other hand, last group (III) are the isolates GI-4 and NE2-37 which have similar growth morphology with Group II except that their viscosity was intermediate between liquid and mucoid. All the isolates produced alkaline substances when grown on YMA plate with BTB which is an indication of the Bradyrhizobium genus.
Characterization of the morphology of the indigenous bradyrhizobia isolated from Philippines’ soil according to their growth on Yeast-Extract Mannitol Agar plate medium [30].
As seen in Figure 1, it is evident that the 11 most abundant indigenous soybean rhizobia in the Philippines are classified under the genus Bradyrhizobium, and are separated into its two species, B. japonicum and B. elkanii, according to the phylogenetic tree from the sequence analysis of the 16S rRNA gene. To further confirm the classification of the indigenous bradyrhizobia, the phylogenetic trees constructed from the ITS region and the rpoB gene are presented in Figures 2 and 3, respectively. For the ITS region and the rpoB gene, the isolates were distinctly grouped into three species, B. elkanii, B. japonicum, and B. diazoefficiens. Additionally, an independent cluster composed of the representative isolates GI-4 and NE2–37 that are seen in the ITS region and rpoB phylogenetic trees were treated as Bradyrhizobium sp. due to their nucleotide divergence with the known species from the BLAST engine.
Phylogenetic tree based on the sequence analysis of the 16S rRNA gene. The tree was constructed using the Neighbor-Joining method with the Kimura 2-parameter (K2P) distance correlation model and 1000 bootstrap replications in MEGA v.7 software. The accession numbers are indicated only for sequences obtained from BLAST. The isolates in this study are indicated with letters and number combinations, for example: BO-4–isolate no. 4 collected from Bohol.
Phylogenetic tree based on the sequence analysis of the 16S-23S rRNA internal transcribed spacer (ITS) region. The tree was constructed using the Neighbor-Joining method with the Kimura 2-parameter (K2P) distance correlation model and 1000 bootstrap replications in MEGA v.7 software. The accession numbers are indicated only for sequences obtained from BLAST. The isolates in this study are indicated with letters and number combinations, for example: BO-4–isolate no. 4 collected from Bohol.
Phylogenetic tree based on the sequence analysis of the rpoB housekeeping gene. The tree was constructed using the Neighbor-Joining method with the Kimura 2-parameter (K2P) distance correlation model and 1000 bootstrap replications in MEGA v.7 software. The accession numbers are indicated only for sequences obtained from BLAST. The isolates in this study are indicated with letters and number combinations, for example: BO-4–isolate no.4 collected from Bohol.
Meanwhile, the distribution of the most abundant soybean bradyrhizobia in the country is shown in Table 3, which was classified according to the results of the sequence analysis of the three genetic markers used in this study. From here, it can be seen that 4 of the 11 locations were dominated with B. elkanii species (37.74%), 3 locations were dominated by the isolates under the B. diazoefficiens (28.54%), whereas 2 locations each were dominated by the species of B. japonicum (16.98% and Bradyrhizobium sp. (16.74%). This indicated that in the Philippines, the species of B. elkanii is the most prevalent in terms of population and the most widespread in terms of location as its presence was detected even in minor populations on all the locations except for one, which was Sorsogon.
Percentage distribution of the dominant Bradyrhizobium species in the Philippines as identified from the sequence analysis of the 16S rRNA gene, 16S-23S internal transcribed spacer (ITS) region, and rpoB housekeeping gene.
Upon classification, it is important to determine the capability of the indigenous bradyrhizobia for their symbiotic performance and N-fixation ability. As can be seen in Figure 4A, although USDA110 strain has the highest N-fixation ability, it should be noted that the amount of N that was fixed by B. elkanii IS-2 is the highest among all the indigenous bradyrhizobia isolated from the Philippines’ soil on Rj4 plants. However, the N-fixation ability of IS-2 was comparably similar with other strains (GI-4, NE2–37, and SK-5) with the non-Rj plants. The lowest N-fixation ability was observed from the strain LT-3 which was classified under the B. diazoefficiens species. This suggested that the process of biological N-fixation is a mutual relationship that is influenced by both the plant and the rhizobia and that the plant-rhizobia compatibility should be taken into consideration for inoculation strategies.
Characterization of the dominant indigenous Bradyrhizobium strains isolated from the 11 locations in the Philippines based on the (A) amount of Nitrogen fixed (B) nodulation ability and (C) symbiotic efficiency as influenced by the single-strain inoculation test against the reference strain B. diazoefficiens USDA110 for the two soybean cultivars from the Philippines. Different letters indicate a significant difference by Tukey’s test at p > 0.05, n=3, bar=SE.
Presented in Figure 4B is the nodulation test performed on the strains and it can be seen for Rj4 plants, there was not much significant difference in the nodulation ability of the strains, except for the low nodulation ability that was observed for the BO-4. In contrast, a significant difference in the nodulation ability was detected on the strains upon inoculation on the non-Rj plants. Although all the strains were able to form nodules on both soybean cultivars, the strains GI-4, NR-2, and SK-5 obtained the highest number of nodules for the non-Rj plants.
On the other hand, the symbiotic efficiency of the strains used in this study is presented in Figure 4C. Similar with the N-fixation ability, the USDA110 still possesses the highest symbiotic efficiency. But among all the indigenous bradyrhizobia, the strain IS-2 obtained the highest efficiency regardless of the Rj genotype of the soybean plants. As with the N-fixation, LT-3 obtained the least efficiency for symbiosis. This result indicated that the symbiotic efficiency of the rhizobia might not be directly influenced by the Rj genotype of the plant.
The distribution of the most dominant and abundant species of soybean bradyrhizobia in the Philippines are reported in this study along with the characterization of their growth morphology. According to our earlier reports, we have elucidated that the Philippines was dominated by the soybean-nodulating bradyrhizobia that were classified under the B. elkanii species and the most important agro-environmental factors that affected their diversity and prevalence in the country was the similarity of soil pH, salinity, and temperature in the study locations [5, 14]. Our observation that there are abundant and high diversity of indigenous bradyrhizobia in the Philippines is similar with previous reports in other sub-tropical and tropical regions [12, 25, 41, 42, 43, 44]. The temperate regions of Japan and USA were studied in the past and were reported to be dominated by species of B. japonicum and B. diazoefficiens [6, 9, 10, 11, 13, 45]. Our report showed that the distribution of bradyrhizobia in a tropical region like the Philippines seemed to be different from those of temperate regions.
Meanwhile, it was included in a recent report that the distribution and abundance of B. diazoefficiens and B. japonicum at specific locations were due to the longer period of flooding conditions [14]. The effect of nutrient content and soil type were also correlated with the abundance of these two species. In a report by Shiina et al. [17], it was stated that the predominance of B. diazoefficiens was observed on more anaerobic condition; whereas, B. japonicum was predominant on aerobic soils which was supported by another study [18]. Additionally, it was reported that B. diazoefficiens becomes predominant with enhanced flooding condition [15]. These results confirmed that our observations for the abundant of B. diazoefficiens, followed by B. japonicum and Bradyrhizobium sp. on flooded areas in the country which were usually used for planting rice.
In this report, the symbiotic performance, N-fixation and nodulation ability of the indigenous soybean bradyrhizobia form the Philippines were evaluated against that of the B. diazoefficiens USDA110 strain. The USDA110 has been extensively used in the world as a model strain for soybean inoculation due to its high ability for N-fixation and symbiotic efficiency [25, 46, 47]. Additionally, its possession of a complete set of denitrification genes that allows the release of N2 back into the atmosphere makes it an ideal strain also for climate change mitigation studies [17, 48, 49, 50].
Therefore, we hypothesized that the indigenous isolates SO-1, LT-3, and SK-5, which were phylogenetically clustered under the USDA110 would also prove to be as effective N-fixer and efficient microsymbiont of soybean cultivars from the Philippines. However, our results indicated that the N-fixation ability and symbiotic efficiency of LT-3 and SO-1 were very low in comparison to the other indigenous isolates. For the low performance of these two isolates, it is hypothesized that the inherent ability of these strains to fix N and establish a symbiotic relationship with soybean is low. This could be explained by the fact that their nodulation ability was comparably similar with the other strains which possess higher N-fixation ability and symbiotic efficiency. In contrast, the isolate IS-2, which was clustered under the B. elkanii species, showed the highest symbiotic efficiency for both Rj-genotypes of the soybean cultivar used and the highest N-fixation ability for Rj4 plants. In a previous report, the Rj genes that could restrict the nodulation of soybean by some strains of bradyrhizobia was summarized [51] but in case of our present report, all the strains in this study were not restricted by the two Rj-plants that were used. This led us to consider that the low N-fixation and symbiotic performance of some strains were not due to the restrictions from the Rj-genotypes of the plants but could be attributed to the strains’ intrinsic capabilities. These observations might explain the reason for low yield of soybean in the Philippines. It was reported that many strains of B. elkanii were relatively inefficient microsymbionts of soybean and can induce chlorosis in soybean plants [52]. In a previous report [53], the high temperatures in tropical regions can limit the nodulation which could explain the low soybean yield.
It was expected that the strains which were classified as B. diazoefficiens could provide a better symbiotic performance than the other strains that were collected. However, the data showed that B. elkanii might establish a better symbiosis with local soybean cultivars in the Philippines. This result is crucial in order to devise strategies on how to increase the local production of soybean by inoculation with the indigenous strains.
Upon considering these results with the N-fixation and symbiotic performance ability of the strains, the number of nodules that can be formed from the single-strain inoculation does not seem to influence the amount of N that each strain can fix nor their symbiotic ability.
In this report, we have revealed that the distribution of tropical soybean bradyrhizobia seemed to be different than those of temperate bradyrhizobia in terms of population dominance of B. elkanii on higher temperature region like the Philippines. Additionally, it is proposed that for the Philippines, the most efficient N-fixer and symbiotically efficient species of bradyrhizobia would be B. elkanii. Yet, our results were made under the laboratory conditions only, so the results that were obtained here might not be as expected when done in field condition. For future research, utilization of more local soybean varieties with different soil types both in a controlled environment and on natural field condition would be beneficial to target the development of a site-specific and useful potential soybean inoculant. The data generated in this report would be beneficial for the augmentation of inoculation strategies in the country.
The authors would like to acknowledge the contributions of John Philip Tanay, Emmanuel Victor Buniao, Mary Joy Portin, and Maria Leah Sevilla of Central Luzon State University for their help on some laboratory experiments. This work was supported by the JSPS Grant-in-Aid for Scientific Research (KAKENHI Grant Number: 18K05376).
The authors declare no conflict of interest.
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n1. RETRACTIONS
\\n\\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
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\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n3. CORRECTIONS
\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
\\n\\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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