1. Introduction
Prostaglandins, hormone-like substances initially isolated from human semen in 1930, got their name from the presumption that they predominately come from the prostate gland (von Euler 1936). In fact, prostaglandins are lipid mediators generated by a wide variety of cell types and tissues. Being derivatives of 20 carbon fatty acids, their common feature is 20-carbon skeleton which includes 5-member carbon ring. Prostaglandins are major players in human physiology in both healthiness and illness and are key molecules in the generation of the inflammatory response (Miller 2006). Their synthesis is drastically increased in inflamed tissue and prostaglandin-mediated signaling contributes to the development of acute inflammation (Ricciotti and Fitzgerald 2011). Prostaglandins regulate a number of principal signal transduction pathways that modulate progression of renal diseases: cellular adhesion, growth, and differentiation. Cyclooxygenases (also termed PGH2 synthases) are key enzymes in the production of prostaglandins from arachidonic acid and an immediate product of cyclooxygenase activity, prostaglandin H2 (PGH2), is used as a substrate by a number of terminal prostaglandin- and thromboxane synthases to produce a whole series of potent bioactive prostanoids. Multiple extracellular mitogens, including PDGF and endothelins, are involved in the pathogenesis of proliferative forms of glomerulonephritis. They share ability to induce Cox-2 expression in glomerular cells resulting in the release of prostanoids, with PGE2 being a major prostaglandin produced by renal cells. Selective Cox-2 inhibitors have an anti-inflammation effect and reduce manifestation of experimental membranous glomerulonephritis. This chapter will discuss the role of prostaglandin synthesis and signaling via specific prostaglandin receptors in the progression of different types of glomerulonephritis.
2. Cellular synthesis of prostaglandins
Arachidonic acid is released from membrane glycerophospholipids by phospholipase A2 and is converted to PGH2 by cyclooxygenases in two steps. Firstly, it is catalyzed to the cyclic endoperoxidase, prostaglandin G2 (PGG2), via an intermediate radical. After that PGG2 is further transformed to PGH2 by a peroxidase reaction (Fig.1). Remarkably, cyclooxygenase molecule possesses two distinct active sites which are responsible for both steps (Marnett et al. 1999; Smith et al. 2000). The cyclooxygenase active site appears to be an L-shaped hydrophobic channel which contains active-site Tyr-385 shown to be directly involved in catalysis, whereas other residues in the active-site are controlling arachidonic acid positioning to ensure that PGG2 is produced, not hydroperoxide side products (Thuresson et al. 2001). Both radical abstraction by a tyrosyl radical and combined radical/carbocationic models have been proposed for this reaction, but a combined radical/carbocation mechanism seems to be less likely (Silva et al. 2007). Generation of tyrosyl radical at Tyr-385 at cyclooxygenase active site is a consequence of oxidation of the heme group at the peroxidase active site by a hydroperoxide. The peroxidase site activity catalyzes the two-electron reduction of the hydroperoxide bond of PGG2 to produce the PGG2 and as indicated by site-directed mutagenesis the conserved cationic pocket is involved in enzyme-substrate binding (Chubb et al. 2006). Since cyclooxygenases function as homodimers and each monomer contains its own cyclooxygenase and peroxidase active sites, one would expect to have four total active sites per functional unit (dimer) of enzyme. On the contrary, it was shown, that while enzyme monomers comprising a dimer are identical in the resting enzyme, they differ from one another during catalysis: the nonfunctioning subunit provides structural support enabling its partner monomer to catalyze the cyclooxygenase reaction (Yuan et al. 2006). Each monomer of the functional
cyclooxygenase homodimer attaches to the endoplasmic reticulum or nuclear envelope membrane through membrane binding domain which contains the main route of substrate entry into the cyclooxygenase active site (Menter et al. 2010; Spencer et al. 1999; Chandrasekharan and Simmons 2004). Being a relatively unstable intermediate, PGH2 is rapidly converted to distinct prostanoids by corresponding terminal prostaglandin synthases (Helliwell et al. 2004). Five major active prostanoids produced in vivo are PGF2
Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase isoforms and act as competitive active site inhibitors (Ricciotti and Fitzgerald 2011). It is believed, however, that NSAIDs have their anti-inflammatory, analgesic and antipyretic effects due to inhibition of Cox-2. There is a lot of interest in NSAIDs as possible accessories to cancer chemotherapy (Moore and Simmons 2000; Subbaramaiah et al. 1997; Thun et al. 2002) and they were shown to reduce incidence of colon cancer (DuBois et al. 1998). Still their undesirable side effects such as gastrointestinal ulceration, bleeding and platelet dysfunctions (due to inhibition of Cox-1) drastically limited enthusiasm about them as anti-cancer drugs. Since a new class of Cox-2 selective inhibitors (COXIBs) which preferentially inhibit the Cox-2 with significantly reduced side effects became available, these compounds have emerged as an important therapeutic tool for treatment of pain and arthritis (3). Again, the initial excitement about Cox-2 selective inhibitors has diminished in recent times because it became clear that their use is associated with an increased cardiovascular risk (Fitzgerald 2004; Furberg et al. 2005). Furthermore, COXIBs can probably act independently of their effect upon Cox-2 (Hanif et al. 1996) leaving physicians uncertain about mechanism of their action.
Biologically active prostaglandins regulate various physiological functions outside kidney which are of principal significance for embryo development, performance of cardiovascular and nervous systems and multiple other biological processes not necessarily connected with renal pathologies. The aim of current chapter is to evaluate the role of Cox-2 activity in the progression of glomerulonephritis and analyze contribution of signaling pathways initiated by particular prostaglandins to the manifestation of the disease. We will also discuss regulation of glomerular prostaglandin synthesis both by regulation of Cox-2 expression and by interaction of Cox-2 with specific proteins spatially co-localized with the enzyme in its natural environment. The significance of the discussed issues is that this cellular regulation of prostaglandin synthesis is an important contributor to the progression of glomerular renal diseases.
3. Renal effects of prostaglandins
3.1. Signaling by prostaglandins
Newly synthesized prostaglandins are crossing the membrane two times: first they are secreted into the extracellular space and later on operate as local hormones in the locality of their production site and again enter the cell prior to inactivation. The efflux could be maintained by simple diffusion, but often is facilitated by several prostaglandin carriers – transporters, which maintain energy-dependent prostaglandin transport across the plasma membrane (Schuster 2002). The common feature of all extracellular prostaglandins is that they accomplish their biological task via binding and activation of seven transmembrane domain G-protein coupled receptors (GPCR), of which eight types and subtypes (FP, DP, IP, TP and EP1-4) are known (Narumiya et al. 1999). The rank order of affinity of prostaglandin ligands to their receptors is known and roles of individual receptors were established in individual mice knockdown systems (Kobayashi and Narumiya 2002). The mouse FP receptor binds PGF2
3.2. Renal expression of prostaglandin receptors
Since focus of our attention is renal action of prostaglandins, intra-renal distribution of only prostaglandin receptors FP, EP1-4 and DP will be discussed. For information about thromboxane TP and prostacyclin IP receptors please look at the excellent review by Breyer and Breyer (Breyer and Breyer 2001) and recent update by Nasralla and co-authors (Nasrallah et al. 2007). Using RT-PCR analysis and immunohistochemistry intra-renal distribution was established for the majority of prostaglandin receptors and transporters (Fig.2).
3.2.1. EP1 receptors
EP1 is expressed in glomerulus, collecting duct and vasculature (Breyer and Breyer 2001). Northern blotting indicated EP1 expression in glomerular mesangial cells (Ishibashi et al. 1999). In reverse transcription-PCR studies, podocyte mRNA for the EP1 could be amplified (Bek et al. 1999). In a mouse model of accelerated antiglomerular basement membrane (anti-GBM) nephrotoxic serum (NTS) nephritis EP1 knockout resulted in stronger impairment of renal function (Rahal et al. 2006). EP1 receptor immunoreactiviy is found in human renal tissue mainly in connecting segments, cortical and medullary collecting ducts, as well as in the media of arteries and afferent and efferent arterioles (Morath et al. 1999). It is not found in either proximal tubules, or thin limbs, thick ascending limbs of Henle's loop or distal convoluted tubules (Morath et al. 1999). It is able to mediate pain perception and regulate blood flow (Stock et al. 2001).
3.2.2. EP2 receptors
The exact intra-renal distribution of EP2 receptors is not entirely defined. Northern blot analysis of EP2 mRNA distribution suggested diffuse expression with no specific increased localization in any particular segments of nephron (Breyer and Breyer 2001). RT-PCR analysis of microdissected rat nephron segments implied EP2 expression in Henle's loop and in vasa recta of the outer medulla (Jensen et al. 2001). Immunolocalization data demonstrated prominent staining of EP2 receptor only in the media of human arteries and of glomerular arterioles whereas staining of other structures of renal cortex or medulla was negative (Morath et al. 1999). It is interesting, that whereas EP2 receptor is hard to detect in normal human kidney, EP2 receptor expression was prominent in cystic epithelial cells lining cysts in polycystic kidney tissue from patients with autosomal-dominant polycystic kidney disease (Elberg et al. 2007).
3.2.3. EP3 receptors
There are more than six alternatively spliced variants of EP3 receptor in humans which differ by unique COOH-terminal intracellular tails (Breyer and Breyer 2000). By in situ hybridization and reverse-transcription PCR the intra-renal location of EP3 receptor was shown to be the thick ascending limb (TAL) and collecting duct. Immunohistochemistry confirmed expression of EP3 receptor in late distal convoluted tubules and in cortical and medullary collecting ducts (Morath et al. 1999).
3.2.4. EP4 receptors
EP4 receptor mRNA is found predominately in glomerulus. Like EP2 receptors, EP4 signals through increase of cAMP production, but it is much more abundant (Breyer and Breyer 2000). The strongest expression of the human protein was detected in smooth muscle cells of arteria, vasa recta and in glomerulus (Morath et al. 1999). In glomerulus EP4 is detected in mesangial cells and podocytes (Ishibashi et al. 1999; Bek et al. 1999).
3.2.5. FP receptors
Studies using FP receptor promoter driving a β-galactosidase reporter indicated that these receptors are expressed in distal convoluted tubule (Breyer and Breyer 2001). Expression of gene encoding FP receptor in distal convoluted tubule and cortical collected duct was further confirmed by in situ hybridization, whereas glomeruli, proximal tubules, or thick ascending limbs showed no expression (Saito et al. 2003; Hebert et al. 2005a).
3.2.6. DP receptors
Even though DP receptor renal localization has not been shown for any species (Breyer and Breyer 2001), indirect evidence (altered tubular transport and haemodynamic effects of infused PGD2) suggest the presence of renal DP receptors (Nasrallah et al. 2007).
3.3. Renal effect of PGE2
3.3.1. Non-glomerular renal effect of PGE2
It is sometimes difficult to distinguish glomerular and non-glomerular effects of prostaglandins, since even when the target cells are located outside the glomerulus, prostaglandin-mediated signaling events could be still relevant for the maintenance of glomerular function. For example changes in vascular tone could contribute to hypertension, which affects glomerular filtration rate. For the purposes of this review we consider effects of prostaglandins to be non-glomerular, if target cells are localized outside the glomeruli. PGE2 is indisputably the most abundant kidney prostaglandin and since, in addition, it signals via four distinct subtypes of EP receptors, the renal effects of PGE2 are multiple and complex. Furthermore, some of non-renal PGE2 effects were abolished by inhibitors of EGF receptor tyrosine kinase indicating that transactivation of EGF receptor is part of the complex response to PGE2 (Buchanan et al. 2003; Ding et al. 2005; Han et al. 2006). PGE2-mediated transactivation of EGF receptor can’t be ruled out for renal effects of PGE2 either. Adding additional level of complexity, heterodimerization of EP1 with β2-adrenergic receptors was reported (McGraw et al. 2006). Probably the most important renal non-glomerular roles of PGE2 are regulation of tubular transport processes along the nephron and regulation of vascular tone (Nasrallah et al. 2007). Availability of knockout mice deficient in each EP subtype facilitated understanding the role of each receptor subtype in renal and non-renal effects of PGE2 (Sugimoto and Narumiya 2007; Kobayashi and Narumiya 2002). Thus, studies of mice deficient in each EP subtypes demonstrated that EP4 receptor mediates renin secretion and that signaling via EP1, EP3, and EP4 receptors contributes to increased PGE2-mediated salt and water excretion in the model of hyperprostaglandin E syndrome/antenatal Bartter syndrome, a renal disease which is characterized by NaCl wasting, water loss, and hyperreninism (Nusing et al. 2005). In another study on isolated perfused kidneys from knockout mice both EP2 and EP4 stimulated renin secretion and all four subtypes were controlling renal vascular tone: EP1 and EP3 receptors were increasing it, whereas EP2 and EP4 were decreasing it (Schweda et al. 2004). Afferent arteriole diameter responses to vasoconstrictor peptide Endothelin-1 were enhanced in mice deficient in EP2 receptor, indicating that PGE2 vasodilative activity is handled at least partially through EP2 (Imig et al. 2002). Similar data was obtained using mice deficient in microsomal PG synthase-1 (PGE synthase), enzyme responsible for converting PGH2 into PGE2. In these mice a 7 day AngII infusion at 0.35 mg/kg per day via osmotic minipump induced marked hypertensive response, which did not occur in wild type mice, suggesting that PGE2 attenuates Ang II-induced vasoconstriction, probably because of inhibition of NADPH oxidase-dependent ROS production (Jia et al. 2008). Basal renal hemodynamics was not affected by EP2 deficiency, but absence of EP3 caused significant increase in basal renal blood flow. EP3 receptor mediates vasoconstriction in the kidney, controls renal blood flow in basal state and buffers PGE2-mediated renal vasodilation (Audoly et al. 2001).
Sodium reabsorption by epithelial Na+ channels (ENaC) located on the apical membrane of kidney distal and collecting duct plays central role in the maintenance of the extracellular fluid volume. Two classes of arachidonic acid metabolites, those produced by cytochrome P 450 enzymes (HETEs and EETs) and those generated by cyclooxygenases (prostaglandins) have opposite effect upon ENaC activity (Wang et al. 2009). 11,12-EET, 8,9-EET and 14,15-EET significantly inhibited ENaC NPo (probably due to direct and very fast interaction between EETs and ENaC) whereas PGE2 had stimulatory effect and acted via second messengers (such as cAMP) (Wang et al. 2009). The Na+ balance and ENaC status are determined by interplay of the formation and actions of these two types of lipid mediators. PGE2 also regulates (through Gs-coupled EP2 and Gq-coupled EP1) expression of ion carrier Na+/K+-ATPase (Nasrallah et al. 2007; Matlhagela and Taub 2006). On the transcriptional level PGE2 was stimulating expression of β subunit of Na+/K+-ATPase encoded by the ATP1B1 gene.
PGE2 also stimulates a number of anti-apoptotic signaling cascades in a variety of renal cells. Well established anti-apoptotic effect of Cox-2 is mediated as a general rule by anti-apoptotic signaling by PGE2. Thus, in the process of autosomal-dominant polycystic kidney disease PGE2 is released to cyst fluid, binds to EP2 receptor, causes synthesis of cAMP and protects cystic epithelial cells from apoptosis eventually leading to cyst expansion (Elberg et al. 2007). Renal medullary interstitial cells are under significant osmotic/mechanical stress
3.3.2. Contribution of signaling pathways initiated by PGE2 to the manifestation of the glomerulonephritis
Different types of glomerulonephritis could be classified based on their clinical presentation or histopathology (Khanna 2011). Regardless glomerulonephritis etiology, the deterioration of renal function is often accompanied by a number of pathological processes which all contribute to the progression of renal injury. These prominent features include the progressive accumulation of extracellular matrix components, inflammatory changes, and in several types of glomerulonephritis also proliferation of glomerular mesangial cells and podocytes injury or proliferation (Kurogi 2003; Alchi and Jayne 2010; Couser and Johnson 1994; Gomez-Guerrero et al. 2005; Bariety et al. 2005). In this and similar sections we will review the potential contribution of particular prostaglandin to the signaling cascades underlying these pathological changes.
PGE2 had pronounced mitogenic effect upon glomerular mesangial cells (Floege et al. 1991a; Floege et al. 1991b) and also induced DNA synthesis in glomerular core preparations enriched in mesangial cells (Mahadevan et al. 1996). The role of PGE2 in accumulation of the extracellular matrix and structural components of glomerular basement membrane in glomeruli observed in patients with hypertensive syndromes of pregnancy has been suggested long ago (Foidart et al. 1983). Urinary concentrating functions were studied in EP3 deficient mice and these mice did not loose their ability to concentrate and dilute urine normally in response to physiological stimuli, but urinary osmolarity increased significantly in wild type mice, but not in EP3 null mice after inhibition of prostaglandin production by indomethacin (Fleming et al. 1998). PGE2 signaling through EP4 receptors mediates podocyte injury and affects the glomerular filtration barrier (Stitt-Cavanagh et al. 2010).
PGE2 is synthesized from PGH2 by terminal PGE synthase mPGES-1. Since deletion or inhibition of mPGES-1 strikingly reduced inflammatory response in mouse models, PGE2 emerged as an important mediator of inflammation (Ricciotti and Fitzgerald 2011). The progression of glomerulonephritis is accompanied by inflammation and enhanced production of PGE2, is likely to contribute to inflammatory response, but the majority of studies using mPGES-1 null mice which link PGE2 to inflammation did not focus on kidney injury (Ricciotti and Fitzgerald 2011). In a recent study mPGES-1 null mice were found to be protected from cisplatin induced nephrotoxicity, but not from acute kidney injury caused by ischemia-reperfusion or endotoxin (Jia et al. 2011). Direct evidence of PGE2 involvement in inflammation will come from an analysis of experimental model of glomerulonephritis induced in mPGES-1 null animals. Due to the signaling via different receptors, PGE2 is capable of both promoting and opposing the inflammatory response in several disorders (Ricciotti and Fitzgerald 2011; Milatovic et al. 2011)
3.4. Renal effect of PGF2α
3.4.1. Non-glomerular renal effect of PGF2α
PGF2
3.4.2. Contribution of signaling pathways initiated by PGF2α to the manifestation of the glomerulonephritis
Since PGF2
3.5. Renal effect of PGD2
3.5.1. Non-glomerular renal effect of PGD2
There are not many reports about PGD2 function in kidney. This prostaglandin is among major products of cyclooxygenases in macrophages and in bone marrow and is likely to play role in immunological responses (Padilla et al. 2000). It is capable to be converted to prostaglandin 15-deoxy-delta 12,14-PGJ2 (15d-PGJ2) that interacts with peroxisome proliferator-activated receptor γ (PPARγ) to promote ROS production and apoptosis in kidney proximal tubule cells (Padilla et al. 2000; Nasrallah et al. 2007). PGD2 inhibited TGFβ1-induced epithelial-to-mesanchymal transition in MDCK cells (Zhang et al. 2006). In samples of renal papillary tissue PGD2 modulates phosphatidylcholine biosynthesis through ERK and PLD activation (Fernandez-Tome et al. 2004).
3.5.2. Contribution of signaling pathways initiated by PGD2 to the manifestation of the glomerulonephritis
In cultured mesangial cells 15d-PGJ2, derivative of PGD2, inhibited IFNγ-stimulated generation of cytokines presumably by targeting JAK/STAT signaling (Panzer et al. 2008). Since synthetic PPARγ ligands failed to produce similar effect, it is likely that in this case 15d-PGJ2 acted independent of PPARγ interaction. Nevertheless, PPARγ, and correspondingly 15d-PGJ2, was shown to play protective role in glomerular diseases (Chung et al. 2005). PPARγ is known to form heterodimers with 9-cis-retinoic acid receptor (RXRα) and, following ligand activation, to bind to PPARγ-responsive element (PPRE) which are present in the promoters of it’s target genes (Kliewer et al. 1992). In addition PPARγ is also capable to antagonize the activities of other transcription factors (AP-1, STAT, NF-κB) and thus influence gene expression indirectly (Ricote et al. 1998). Although the pathogenesis of glomerulosclerosis is elusive, the imbalance between ECM synthesis and dissolution is the critical determinant of matrix accumulation. This net matrix turnover reflects rapid and specific changes in gene expression controlled by transcription factors that mediate various pathways of cellular injury. PPARγ is such a factor and has recently attracted significant attention for its anti-inflammatory and anti-fibrotic effects against diverse injuries in kidney, liver, lung and heart (Chung et al. 2005; Sugawara et al. 2010). The most recognized renal effect of agonists of PPARg on diabetic nephropathy is as a rule related to the improved glucose metabolism and insulin resistance. But, there is mounting evidence now that PPARγ also elicits nonmetabolic functions in the progression of glomerular diseases. Thus, PPARγ activation prevented albuminuria and enhanced glomerular ECM gene expression in models of both insulin dependent and independent diabetes and in 5/6 nephrectomized rats (Imano et al. 1998; Ma
3.6. Non-receptor action of prostaglandins
Even though prostaglandins act as a rule through their specific receptors, some effects of prostaglandins may be non-receptor-mediated. Several studies implied that prostaglandins exerted their diverse effects through post-translational modification of cellular proteins (Kim et al. 2007; Takahashi and Breitman 1992; Lecomte et al. 1990). Since prostaglandins possess anionic moieties at physiological pH and diffuse poorly through the lipid bilayer (Baroody and Bito 1981; Chan et al. 1998), the covalent modification of proteins by prostaglandins should be a carrier-mediated transport process. Several prostaglandins carriers have been cloned and characterized (Schuster 2002). Prostaglandin uptake carrier prostaglandin transporter (PGT) was shown to be expressed in renal collecting ducts and to participate in prostaglandin metabolic inactivation (Nomura et al. 2005). Another transporter designated OAT-PG exhibited Na+-independent and saturable transport of PGE2 and was shown to be present exclusively in the basolateral membrane of the proximal tubules in the kidney (Shiraya et al. 2010) (Fig.2). As others prostaglandin transporters, OAT-PG was proposed to be involved in the local PGE2 clearance and metabolism for the purpose of inactivation of prostaglandin signals in the kidney cortex, but signaling from PGE2 transported into the cell can’t be ruled out. The covalent binding of prostaglandins to proteins has been detected in microsomal cell fractions and in intact platelets (Eling et al. 1977; Wilson et al. 1979; Anderson et al. 1979). It was demonstrated that proteins in HL-60 cells were labeled by PGE2 (Takahashi and Breitman 1992). PGE2 possesses a long-chain fatty acid portion that could bind covalently to proteins by an ester bond between its carboxyl group and either a hydroxyl amino acid or a cysteine of a protein. No data, so far, suggest the role of PGE2-mediated modification of proteins in the progression of renal pathologies. Nevertheless prostaglandin-mediated modification of signaling molecules involved in the progression of glomerulonephritis can’t be ruled out and should be kept in mind when renal effects of prostaglandins are observed in cells in the absence of detectable receptors, or in the presence of specific receptor inhibitors/antagonists.
4. Renal regulation of prostaglandin synthesis
4.1. Regulation at the level of availability of arachidonic acid
Liberation of free arachidonic acid from glycerophospholipids is catalyzed by phospholipase A2 enzymes and presents the initial tightly regulated step in the synthesis of prostaglandins (Shimizu and Wolfe 1990). The diverse phospholipase A2 enzymes have been classified into eleven groups (Six and Dennis 2000), but cytosolic phospholipase A2α (cPLA2α), member of Group IV, preferentially hydrolyzes the sn-2 position of glycerophospholipids to produce free arachidonic acid, substrate for cyclooxigenase enzymes (Hirabayashi et al. 2004). Mice deficient in cPLA2α grow normally but are characterized by renal concentration defect and cells derived from these mice produce significantly less amount of prostaglandins (Uozumi and Shimizu 2002). Regulation of cPLA2α occurs mainly by phosphorylation of regulatory serines, by increasing intracellular Ca+2 concentrations and changes in enzyme subcellular localization (Hirabayashi et al. 2004). The requirement for extracellular Ca+2 and stretch-activated Ca+2 channels was shown for cyclic stretching-induced PLA2 activation and a subsequent release of arachidonic acid in rabbit proximal tubular epithelial cells (Alexander et al. 2004). Calcium binding to cPLA2α promotes its translocation to membrane containing phosphatidylcholine from the cytosol. Binding to membrane anionic phospholipids and phosphorylation of cPLA2α by either MAPK on Ser505, or by CaMKII on Ser515, or by MAPK-interacting kinase Mnk1 on Ser727 are needed to stabilize cPLA2α association with the membrane and to increase its intrinsic catalytic activity (Hirabayashi et al. 2004).
4.2. Regulation at the level of cyclooxygenases
It is generally accepted that the major mechanism employed by mammalian cells to regulate prostaglandin synthesis is through the control of expression of Cox-2. It is possible however that some alternative mechanisms regulating Cox-2 activity (and ultimately prostaglandin synthesis) exist and are at least partially responsible for the increased production of prostaglandins in glomerular kidney diseases.
4.2.1. Regulation of cyclooxygenases at the level of transcription
Signaling pathways involved in the regulation of Cox-2 expression are relatively well studied (Tsatsanis et al. 2006). A rapid and transient expression of Cox-2 was found to be associated with activation of NF kappa B and NF-IL6 transcription factors (Yamamoto et al. 1998). The promoter/enhancer region of Cox-2 genes from different mammalian species share a number of modulatory elements, which include cAMP-response element (CRE), nuclear factor (NF)-IL6, NF-κB and activator protein 2 (Kosaka et al. 1994). Three of these consensus sequences (CRE, NF-IL6 and NF-κB) have been implicated in agonist-dependent up-regulation of the human Cox-2 (Kosaka et al. 1994; Inoue and Tanabe 1997; Inoue and Tanabe 1998); additionally it appears that p53 might negatively regulate Cox-2 expression by binding to the TATA sequence (Subbaramaiah et al. 1999). Cox-2 expression is induced by multiple agonists and mitogens including PDGF (Goppelt-Struebe et al. 1996), EGF (Saha et al. 1999), TGFβ1 (Saha et al. 1999) and Endothelin-1 (Kester et al. 1994). It is of note that three principal mitogen activated protein kinase (MAPK) pathways ERK, JNK and p38 MAPK are activated by many of the agonists and stimuli capable of stimulating Cox-2 expression (Bokemeyer et al. 1996; Widmann et al. 1999). Furthermore, a number of MAPK-activated transcription factors are binding to the regions of the promoter of human gene encoding Cox-2 which are involved in the transcriptional activation of the gene (Widmann et al. 1999; Kosaka et al. 1994). Data obtained with adenovirus mediated gene transfer of constitutively active mutants of members of three principal MAPK signaling cascades provided evidence that enforced stimulation of any of them results in up-regulation of Cox-2 expression (McGinty et al. 2000). It looks like MAPK signaling cascades are the convergence point of the many dissimilar stimuli that up-regulate Cox-2.
4.2.2. Regulation of cyclooxygenases at the post-transcriptional pre-translational level
Regulation at the post-transcriptional pre-translational level occurs through regulation of Cox-2 mRNA stability (Tsatsanis et al. 2006). It was reported that signaling via p38 MAPK pathway was controlling Cox-2 mRNA stability (Jang et al. 2000) and occurred through p38 MAPK-regulated binding of mRNA stabilizing protein human antigen R (HuR) to the AU-rich region of the COX-2 3'-UTR (Subbaramaiah et al. 2003). HuR is related to the
4.2.3. Regulation of cyclooxygenases at the post- translational level
It seems that the kinetics of prostaglandin synthesis in mammalian cells does not always correlate with the level of cyclooxygenases expression. This suggested that there maybe alternative mechanisms in the cellular regulation of cyclooxygenases activity and ultimately, prostaglandin synthesis. There are not many reports which suggest regulation of catalytic activity of cyclooxygenases at the post-translational level. Until recently only two examples of post-translational regulation of Cox-2 were reported: s-nitrosylation and phosphorylation. iNOS was shown to bind specifically to Cox-2 and S-nitrosylate it, increasing Cox-2 catalytic activity (Kim et al. 2005). The same group demonstrated that Cox-2 can be activated by S-nitrosylation after selective binding of nNOS to Cox-2 via nNOS PDZ domain (Tian et al. 2008). S-nitrosylation of Cox-2 happened also
First hint that cyclooxygenase could be regulated by phosphorylation was obtained in cerebral endothelial cells where it was demonstrated that protein tyrosine phosphatase inhibitors rapidly stimulated cyclooxygenase activity resulting in elevated generation of prostaglandins. The protein tyrosine kinase inhibitors genistein and tyrphostins inhibited cyclooxygenase activity (Parfenova et al. 1998). It is important that in this study protein synthesis inhibitors were not able to reverse the stimulation of COX activity evoked by PTP inhibitors, suggesting posttranslational modification. The existence of PKC consensus sequences in Cox-2 prompted the investigation whether Cox-2 could be phosphorylated by the serine/threonine protein kinase C (Vezza et al. 1996). The obtained data argued against direct Cox-2 phosphorylation by PKC. Thus, even though some indirect evidence suggests that Cox-2 could be regulated by phosphorylation, no specific tyrosine or serine-threonine kinase has been proven to phosphorylate cyclooxygenases and regulate their activity.
We have observed that adenovirus-mediated gene transfer of Cox-2 into renal glomerular mesangial cells resulted in the formation of covalent adducts between Cox-2 and some unknown proteins (detected as high-molecular weight bands recognized by anti-Cox-2 antibodies in western blotting). Formation of these covalent adducts was dependent on Cox-2 enzymatic activity. To identify these proteins which may be involved in regulation of Cox-2 activity, we isolated Cox-2 adducts by affinity purification with Cox-2 antibody and subjected them to tandem mass spectrometry. A following search against mammalian database indicated the presence of a number of proteins, potential candidates for post-translational regulators of Cox-2 activity. It is possible that cross-linking of Cox-2 to some specific proteins spatially co-localized with the enzyme in its natural environment occurs due to spontaneous decomposition of PGH2 resulting in production of -keto aldehydes – levuglandins, which are capable of covalently crosslinking different proteins together through their Lys residues (Iyer et al. 1989; Salomon and Miller 1985). One of the proteins cross-linked to Cox-2 was identified as ELMO1 (Engulfment and cell motility 1) (Yang and Sorokin 2011). ELMO1 is a bipartite guanine nucleotide exchange factor (GEF) for the small GTPase Rac 1, which is closely associated with susceptibility to glomerular disease (Shimazaki et al. 2005; Leak et al. 2009; Pezzolesi et al. 2009). ELMO1 was shown to increase fibronectin expression and contribute to the development and progression of chronic glomerular injury (Shimazaki et al. 2006). Interaction of endogenous ELMO1 with endogenous Cox-2 was demonstrated in glomerular mesangial cells (Yang and Sorokin 2011). This interaction of ELMO1 with Cox-2 increased Cox-2-mediated fibronectin upregulation, suggesting that ELMO1 serves as a post-translational modulator of Cox-2 activity. Since ELMO1 may participate in ECM accumulation in the pathogenesis of glomerular pathology through modifying Cox-2 activity via protein-protein interaction could play an important role in the development and progression of renal glomerular disease. How exactly interaction with ELMO1 up-regulates Cox-2 activity is not known. One possibility is that interaction with ELMO1 interferes with Cox-2 degradation and preserves Cox-2 for prolonged prostaglandin production. There are two pathways for Cox-2 protein degradation in vivo: Cox-2 can be degraded via the N-glycosylation-dependent endoplasmic reticulum-associated protein degradation pathway or by substrate-dependent degradation which is not inhibited by inhibitors of lysosomal proteases or proteasome inhibitors (Wada et al. 2009; Mbonye et al. 2008). Future investigation into whether ELMO1 protein interferes with these Cox-2 degradation pathways or contributes to Cox-2 conformational changes which affect its enzymatic activity will help to uncover precise mechanism of ELMO1 action.
4.3. Regulation at the level of prostaglandin synthases
The repertoire of prostaglandin production is determined by the differential expression of terminal prostaglandin synthases in cells located at sites of inflammation (Ricciotti and Fitzgerald 2011). In contrast to cyclooxygenases, there is less known about regulation of PGE-, PGD- and PGF-synthases which convert PGH2 to PGE2, PGD2 and PGF2 correspondingly. There are three prostaglandin E synthases (PGES): membrane-bound microsomal PGES-1 (mPGES-1), membrane-bound PGES-2 (mPGES-2) and cytosolic PGES (cPGES) (Kudo and Murakami 2005). mPGES-1 is functionally coupled to Cox-2 in preference to Cox-1 and, similar to Cox-2, mPGES-1 expression can be stimulated by proinflammatory stimuli (Kudo and Murakami 2005). Analysis of mPGES-1 promoter revealed that stimulus-inducible mPGES-1 transcription is under control of the transcription factor Egr-1, which binds to the proximal GC box (Naraba et al. 2002). Signal transduction pathway comprising phosphatidylcholine-phospholipase C, protein kinase C, NO, cGMP and protein kinas G is important for the induction of mPGES-1 by TNFα (Subbaramaiah et al. 2004). mPGES-2 is constitutively expressed, could be coupled either with Cox-1 or Cox-2, and inflammation or tissue damage do not cause increase of mPGES-2 expression (Kudo and Murakami 2005). cPGES is also constitutively expressed but is exclusively coupled with Cox-1. Regulation of cPGES is mediated by phosphorylation by casein kinase 2 (CK2) and Hsp90 acts as an essential scaffold protein to brings cPGES and CK2 in close proximity to allow their efficient functional interaction (Kudo and Murakami 2005). It must be mentioned, that there is some discrepancy in the literature with regard to the role of cPGES and mPGES-2 in PGE synthesis. Analysis of knockout mice deficient in either cPGES or mPGES-2 suggested that cPGES and mPGES-2 do not encode prostaglandin synthases and for that reason mPGES-1-dependent conversion of PGH2 to PGE2 may represent the only mechanism by which PGE2 is produced
5. Effect of glomerulitis on prostaglandin production
5.1. Overexpression of Cox-2 in renal diseases
Overexpression of Cox-2 and increased production of an array of prostaglandins occurs in inflammatory arthritis, several types of cancer, in inflammatory bowel disease (Turini and DuBois 2002) as well as in a number of kidney diseases, namely proliferative glomerulonephritis (Hirose et al. 1998; Chanmugam et al. 1995), hydronephronic kidney (Seibert et al. 1996), hypercalcemia (Mangat et al. 1997), hypertension (Khan et al. 2001), diabetic nephropathy (Nasrallah et al. 2003; Khan et al. 2001) and renal ablation (Schneider and Stahl 1998). In normal kidneys renal Cox-2 expression was shown to localize in the macula densa and associated cortical thick ascending limb and medullary interstitial cells (Harris and Breyer 2001). In patients with active lupus nephritis Cox-2-specific staining was localized mainly in the glomeruli, whereas patients with non-lupus nephropathies had no increase in renal COX-2 expression (Tomasoni et al. 1998).
Oxidative stress is significantly higher in patients with proliferative glomerulonephritis, when compared with patients with non-proliferative glomerulonephritis (Markan et al. 2008). Oxidative stress is associated with excess of reactive oxygen species (ROS) and signaling pathways triggered by ROS can induce up-regulation of Cox-2 expression and prostaglandin production (Jaimes et al. 2008). Isolated glomeruli treated with donor of oxygen radicals increased the synthesis of several prostaglandins including PGE2 and PGF2α (Baud et al. 1981).
5.2. Regulation of prostaglandin synthesis in experimental models of glomerular proliferative diseases
In several in vivo experimental models Cox-2 contributed to progressive kidney injury (Cheng and Harris 2004). Cox-2 inhibition limited progressive injury in 5/6 nephrectomy rats (Fujihara et al. 2003) and also decreased proteinurea and retarded progressive renal injury in rats with renal ablation (Wang et al. 2000). Production of prostaglandins, particularly PGE2, was shown to contribute to both progression (Hirose et al. 1998) and resolution (Hartner et al. 2000) of mesangioproliferative glomerulonephritis (GN). Studies with experimental models of glomerular proliferative diseases suggested that regulation of cellular synthesis of prostaglandins
5.3. Mechanisms of renoprotective effect of Cox-2 inhibition
There could be multiple mechanisms by which inhibition of Cox-2 is renoprotective, but the suppression of apoptotic pathways is certainly one of them. It is of note, that glomerular mesangial cell (GMC) apoptosis appears to be the major mechanism for resolution of glomerular hypercellularity in experimental mesangial glomerulonephritis (Badawi 2000). Proliferation of GMC occurs in multiple forms of glomerular immune injury and if continued unopposed, would cause the progression of injury to end stage disease (Lianos 1992). The cell number in glomeruli is controlled by apoptosis, accordingly cell proliferation is counteracted by deletion of extra cells due to apoptotic cell death (Savill 1999). For that reason the failure to undergo apoptosis usually results in unbalanced glomerular cell multiplication; hence, apoptosis has been proposed as an essential mechanism involved in the resolution of a proliferative response. It seems likely that Cox-2 has anti-apoptotic effect, when expressed in renal glomerular cells. Surely, Cox-2 is not the only mediator of the resistance of renal GMC to apoptosis, but Cox-2, acting in concert with other survival factors is expected to contribute to the balance between increase in cell number caused by proliferation and cell elimination by programmed cell death. Both extrinsic (death-receptor initiated) and intrinsic (mitochondria-induced) apoptotic pathways are relevant to renal disease and both of them are likely to be inhibited by Cox-2. Macrophage-derived TNF-α induced apoptosis of mesangial cells in the course of glomerulonephritis and inhibition of NFκB-driven survival pathway promoted TNF-α apoptotic activity (Hirahashi et al. 2000), suggesting the involvement of Cox-2 expression. TNF-α-mediated apoptosis of cultured renal mesangial cells was prevented by Cox-2 expression, either enforced by adenovirus mediated gene transfer or induced by the vasoconstrictor peptide endothelin-1 or the cytokine interleukin-1β (Ishaque et al. 2003). Selective Cox-2 inhibition by NS-398 restored TNFα-mediated apoptosis, whereas addition of PGE2 mimicked Cox-2 effect (Ishaque et al. 2003).
Even though it is generally accepted that Cox-2 expression has anti-apoptotic effect, the precise mechanism of Cox-2 anti-apoptotic activity is unknown and remains to be the focus of scientific interest of a number of laboratories. Several mechanisms have been proposed to explain the anti-apoptotic effect of Cox-2 (Cao and Prescott 2002), namely: a) depletion of arachidonic acid, which prevents the activation of neutral sphyngomyelinase and production of ceramide (Cao et al. 2000); b) modulation of expression of the anti-apoptotic protein Bcl-2 (Liu et al. 1998; Tsujii and DuBois 1995); c) regulation of Akt activation (Hsu et al. 2000; Lin et al. 2001); d) counteracting NO-mediated apoptotic cell death, either via modulation of expression of prosurvival gene PIN, inhibiting production of NO (Chang et al. 2000), or via regulation of cellular susceptibility toward NO (von Knethen and Brune 1997). Among genes activated in mesangial cells by Cox-2 expression and/or addition of prostaglandins is the multi-drug resistance gene (MDR1) which encodes a protein termed P glycoprotein (P-gp). P-gp belongs to the ATP-binding cassette (ABC) family of transporter molecules, which require hydrolysis of ATP to run the transport mechanism. The substrates of P-gp may be endogenous (steroid hormones, cytokines) or xenobiotics (cytostatic drugs). P-gp is known to confer the drug resistance in cancer cells. Only recently has the role of P-gp expressed in normal tissues has been examined. In the kidney P-gp is present in the brush border membrane of the proximal tubule, a site compatible with a role in xenobiotic secretion (Johnstone et al. 2000a; Ernest et al. 1997). It is also expressed in the mesangium, the thick ascending limb of Henle’s loop, and the collecting duct (Ernest et al. 1997), locations that are not traditionally associated with drug excretion. P-gp may regulate apoptosis, chloride channel activity, cholesterol methabolism and immune cell function (Ernest et al. 1997; Johnstone et al. 2000b; Zager 2001). It was shown that Cox-2 regulated P-gp expression in GMC (Patel et al. 2002) and rescued GMC from apoptosis induced by adriamycin (Miller et al. 2006), suggesting P-gp role in Cox-2-mediated GMC survival (Sorokin 2004). On the contrary, it appears that transgenic mice overexpressing Cox-2 selectively in podocytes were more susceptible to glomerular injury by adriamycin (Cheng et al. 2009). It was suggested that basal Cox-2 is important for podocyte survival, but overexpression of podocyte Cox-2 increases susceptibility to podocyte injury (Cheng et al. 2009).
5.4. Future directions
Even though inhibitors of cyclooxygenases are capable to induce adverse reactions it is unlikely that efforts would stop to develop drugs affecting prostaglandin production which will be free of this negative aspects. If it would be shown that environmental as well as genetic factors may cause interpatient variability in NSAIDs and COXIBs metabolism and therapeutic effect, it would set the stage for personalized treatment of inflammatory diseases including glomerulonephritis. Only few pharmacogenomics reports have been published to date in nephrology and there is a need to build up efforts in this important research field (Zaza et al. 2010). It is reassuring that the susceptibility to crescentic glomerulonephritis was found to be linked to a polymorphism in the promoter region of
Several studies have established unequivocally that certain widely used inhibitors of cyclooxygenases caused anti-inflammatory and antiproliferative effects independent of cyclooxygenase activity and prostaglandin synthesis inhibition (Tegeder et al. 2001). Hence, the possibility to regulate cyclooxygenase activity at the level of protein-protein interactions is of significant interest, because it could set the basis for generation of novel inhibitors of prostaglandin synthesis. A number of signaling proteins, including ELMO1, were identified as candidates for the post-translational regulation of Cox-2 activity. Interaction with ELMO1 increased Cox-2-mediated induction of expression of the extracellular matrix protein fibronectin (Yang and Sorokin 2011). The ability of Cox-2 to induce fibronectin expression depended on the production of PGE2, implying that an interaction with ELMO1 promoted ability of Cox-2 to synthesize prostaglandins. Thus, the role of ELMO1 could be to increase the synthesis of prostaglandins by Cox-2. One could expect that inhibition of ELMO1/Cox-2 interaction would decrease the biological action of Cox-2 and therefore, represent a novel strategy to attenuate Cox-2 activity in inflammatory renal diseases. It is of note, that exposure to pathological stimuli induced glomerular mesangial cells to produce extracellular matrix proteins (ECM), such as collagens, fibronectin and proteinase inhibitors, resulting in the abnormal accumulation ECM in glomerular mesangium and irreversible glomerular injury (Pezzolesi et al. 2009; Wilson et al. 1998).
6. Conclusions
Three major levels of cellular control of prostaglandin synthesis are 1) at the level of liberation of free arachidonic acid from glycerophospholipids; 2) at the level of cyclooxygenases, and 3) at the level of terminal prostaglandin synthases. As a rule, prostaglandins exert their actions through specific G-protein coupled receptors even though direct modification of cellular proteins by prostaglandins was also observed. Intra-renal localization of prostaglandins receptors and their coupling to particular G-proteins and, correspondingly, to specific intracellular signaling pathways determine the outcome of renal action of distinct prostaglandins. There is mounting evidence that progression of glomerulitis is accompanied by increased expression of cyclooxygenases (usually inducible isoform Cox-2) and enhanced production of prostaglandins, which have profound effect upon the survival/functioning of glomerular cells and normal performance of glomeruli. Prostaglandins are major mediators of inflammation and continuing treatment with Cox-2 specific inhibitors usually improves functional and structural damage in experimental models associated with changed renal hemodynamics and progressive renal injury. Even though inhibition of renal prostaglandin production is supposed to be renoprotective, prostaglandins also have antiflammatory properties. Currently used inhibitors of cycclooxygenases are not free from adverse effects and their action is not always explained by inhibition of cyclooxygenase activity and prostaglandin synthesis. Therefore, increased understanding of novel mechanisms of regulation of prostaglandin production (such as regulation of cyclooxygenases at the post-translational level) will set the base for the design of new generation of inhibitors of prostaglandin synthesis and will open novel strategies to combat progression of glomerular renal diseases.
Acknowledgments
This work was supported by grants to A. Sorokin from National Institutes of Health RO1DK41684 and R21DK088018.
References
- 1.
Alchi B. Jayne D. 2010 Membranoproliferative glomerulonephritis.25 1409 1418 - 2.
Alexander L. D. Alagarsamy S. Douglas J. G. 2004 Cyclic stretch-induced cPLA2 mediates ERK 1/2 signaling in rabbit proximal tubule cells.65 551 563 - 3.
Anderson M. W. Crutchley D. J. Chaudhari A. Wilson A. G. Eling T. E. 1979 Studies on the covalent binding of an intermediate(s) in prostaglandin biosynthesis to tissue macromolecules.573 40 50 - 4.
Arun B. Goss P. 2004 The role of COX-2 inhibition in breast cancer treatment and prevention.31 22 29 - 5.
Atar S. Ye Y. Lin Y. Freeberg S. Y. Nishi S. P. Rosanio S. Huang M. H. Uretsky B. F. Perez-Polo J. R. Birnbaum Y. 2006 Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2. 290, H1960 H1968. - 6.
Audoly L. P. Ruan X. Wagner V. A. Goulet J. L. Tilley S. L. Koller B. H. Coffman T. M. Arendshorst W. J. 2001 Role of EP(2) and EP(3) PGE(2) receptors in control of murine renal hemodynamics. 280, H327 H333. - 7.
Badawi AF 2000 The role of prostaglandin synthesis in prostate cancer.85 451 462 - 8.
Bariety J. Bruneval P. Meyrier A. Mandet C. Hill G. Jacquot C. 2005 Podocyte involvement in human immune crescentic glomerulonephritis.68 1109 1119 - 9.
Baroody RA, Bito LZ 1981 The impermeability of the basic cell membrane to thromboxane-B2’ prostacyclin and 6-keto-PGF 1 alpha.21 133 142 - 10.
Basu S. 2010 Bioactive eicosanoids: role of prostaglandin F(2alpha) and F-isoprostanes in inflammation and oxidative stress related pathology.30 383 391 - 11.
Baud L. Nivez M. P. Chansel D. Ardaillou R. 1981 Stimulation by oxygen radicals of prostaglandin production by rat renal glomeruli.20 332 339 - 12.
Behmoaras J. Bhangal G. Smith J. Mc Donald K. Mutch B. Lai P. C. Domin J. Game L. Salama A. BM Foxwell Pusey. C. D. Cook H. T. Aitman T. J. 2008 Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility.40 553 559 - 13.
Bek M. Nusing R. Kowark P. Henger A. Mundel P. Pavenstadt H. 1999 Characterization of prostanoid receptors in podocytes.10 2084 2093 - 14.
Bell P. D. Lapointe J. Y. Peti-Peterdi J. 2003 Macula densa cell signaling.65 481 500 - 15.
Bokemeyer D. Guglielmi K. E. Mc Ginty A. Sorokin A. Lianos E. A. MJ Dunn 1997 Activation of extracellular signal-regulated kinase in proliferative glomerulonephritis in rats.100 582 588 - 16.
Bokemeyer D. Sorokin A. MJ Dunn 1996 Multiple intracellular MAP kinase signaling cascades.49 1187 1198 - 17.
BA Breshnahan Kelefiotis. D. Stratidakis I. Lianos E. A. 1996 PGF2alpha-induced signaling events in glomerular mesangial cells.212 165 173 - 18.
Breyer MD, Breyer RM 2000 Prostaglandin E receptors and the kidney. 279, F12 F23. - 19.
Breyer MD, Breyer RM 2001 G protein-coupled prostanoid receptors and the kidney.63 579 605 - 20.
Buchanan F. G. Wang D. Bargiacchi F. Du Bois. RN 2003 Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor.278 35451 35457 - 21.
Cao Y. Pearman A. T. Zimmerman G. A. Mc Intyre T. M. Prescott S. M. 2000 Intracellular unesterified arachidonic acid signals apoptosis.97 11280 11285 - 22.
Cao Y. Prescott S. M. 2002 Many actions of cyclooxygenase-2 in cellular dynamics and in cancer.190 279 286 - 23.
Carlsen I. Donohue K. E. Jensen A. M. Selzer A. L. Chen J. Poppas D. P. Felsen D. Frokiaer J. Norregaard R. 2010 Increased cyclooxygenase-2 expression and prostaglandin E2 production in pressurized renal medullary interstitial cells. 299, R823 R831. - 24.
BS Chan Satriano. J. A. Pucci M. Schuster V. L. 1998 Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter "PGT".273 6689 6697 - 25.
Chandrasekharan NV, Simmons DL 2004 The cyclooxygenases. 5, 241. - 26.
Chang Y. W. Jakobi R. Mc Ginty A. Foschi M. MJ Dunn Sorokin. A. 2000 Cyclooxygenase 2 promotes cell survival by stimulation of dynein light chain expression and inhibition of neuronal nitric oxide synthase activity.20 8571 8579 - 27.
Chanmugam P. Feng L. Liou S. Jang B. C. Boudreau M. Yu G. Lee J. H. Kwon H. J. Beppu T. Yoshida M. 1995 Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis.270 5418 5426 - 28.
Cheng H. Fan X. Guan Y. Moeckel G. W. Zent R. Harris R. C. 2009 Distinct roles for basal and induced COX-2 in podocyte injury.20 1953 1962 - 29.
Cheng HF, Harris RC 2004 Cyclooxygenases, the Kidney, and Hypertension.43 1 6 - 30.
Chubb A. J. Fitzgerald D. J. Nolan K. B. Moman E. 2006 The productive conformation of prostaglandin G2 at the peroxidase site of prostaglandin endoperoxide H synthase: docking, molecular dynamics, and site-directed mutagenesis studies.45 811 820 - 31.
Chung B. H. Lim S. W. Ahn K. O. Sugawara A. Ito S. BS Choi Kim. Y. S. Bang B. K. Yang C. W. 2005 Protective effect of peroxisome proliferator activated receptor gamma agonists on diabetic and non-diabetic renal diseases. 10 Suppl, S40 S43. - 32.
Couser WG, Johnson RJ 1994 Mechanisms of progressive renal disease in glomerulonephritis.23 193 198 - 33.
Dannenberg A. J. Lippman S. M. Mann J. R. Subbaramaiah K. Du Bois. RN 2005 Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention.23 254 266 - 34.
Datta P. K. Dhupar S. Lianos E. A. 2006 Regulatory effects of inducible nitric oxide synthase on cyclooxygenase-2 and heme oxygenase-1 expression in experimental glomerulonephritis.21 51 57 - 35.
Ding Y. B. Shi R. H. JD Tong Li. X. Y. Zhang G. X. Xiao W. M. Yang J. G. Bao Y. Wu J. Yan Z. G. Wang X. H. 2005 PGE2 up-regulates vascular endothelial growth factor expression in MKN28 gastric cancer cells via epidermal growth factor receptor signaling system.27 108 113 - 36.
Doller A. Gauer S. Sobkowiak E. Geiger H. Pfeilschifter J. Eberhardt W. 2009 Angiotensin II induces renal plasminogen activator inhibitor-1 and cyclooxygenase-2 expression post-transcriptionally via activation of the mRNA-stabilizing factor human-antigen R.174 1252 1263 - 37.
Doller A. Huwiler A. Muller R. Radeke H. H. Pfeilschifter J. Eberhardt W. 2007 Protein kinase C alpha-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2.18 2137 2148 - 38.
Du Bois. RN Abramson S. B. Crofford L. Gupta R. A. Simon L. S. Van De Putte L. B. Lipsky P. E. 1998 Cyclooxygenase in biology and disease.12 1063 1073 - 39.
Elberg G. Elberg D. Lewis T. V. Guruswamy S. Chen L. Logan C. J. MD Chan Turman. MA 2007 EP2 receptor mediates PGE2 induced cystogenesis of human renal epithelial cells. 293, F1622-F1632. - 40.
Eling T. E. Wilson A. G. Chaudhari A. Anderson M. W. 1977 Covalent binding of an intermediate(s) in prostaglandin biosynthesis to guinea pig lung microsomal protein.21 245 251 - 41.
Ernest S. Rajaraman S. Megyesi J. Bello-Reuss E. N. 1997 Expression of MDR1 (multidrug resistance) gene and its protein in normal human kidney.77 284 289 - 42.
Fernandez-Tome M. Favale N. Kraemer L. MM Gabriela Speziale. E. Sterin-Speziale N. 2004 44 ERK1/2) MAPK and PLD activation by PGD2 preserves papillary phosphatidylcholine homeostasis. 320, 1055-1062. - 43.
Fernau N. S. Fugmann D. Leyendecker M. Reimann K. Grether-Beck S. Galban S. Ale-Agha N. Krutmann J. Klotz L. O. 2010 Role of HuR and38MAPK in ultraviolet B-induced post-transcriptional regulation of COX-2 expression in the human keratinocyte cell line HaCaT. 285, 3896-3904. - 44.
Fitzgerald GA 2004 Coxibs and cardiovascular disease.351 1709 1711 - 45.
Fleming E. F. Athirakul K. Oliverio M. I. Key M. Goulet J. Koller B. H. Coffman T. M. 1998 Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2. 275, F955 F961. - 46.
Floege J. Topley N. Resch K. 1991a Regulation of mesangial cell proliferation.17 673 676 - 47.
Floege J. Topley N. Resch K. 1991b Regulation of mesangial cell proliferation.17 673 676 - 48.
Foidart J. M. Nochy D. Nusgens B. Foidart J. B. Mahieu P. R. Lapiere C. M. Lambotte R. Bariety J. 1983 Accumulation of several basement membrane proteins in glomeruli of patients with preeclampsia and other hypertensive syndromes of pregnancy. Possible role of renal prostaglandins and fibronectin.49 250 259 - 49.
Fujihara C. K. Antunes G. R. Mattar A. L. Andreoli N. Malheiros D. M. Noronha I. L. Zatz R. 2003 Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney.64 2172 2181 - 50.
Fujii M. Takemura R. Yamaguchi M. Hasegawa G. Shigeta H. Nakano K. Kondo M. 1997 Troglitazone (CS-045) ameliorates albuminuria in streptozotocin-induced diabetic rats.46 981 983 - 51.
Furberg CD, Psaty BM, Fitzgerald GA 2005 Parecoxib, valdecoxib, and cardiovascular risk. 111, 249. - 52.
Gomez-Guerrero C. Hernandez-Vargas P. Lopez-Franco O. Ortiz-Munoz G. Egido J. 2005 Mesangial cells and glomerular inflammation: from the pathogenesis to novel therapeutic approaches.4 341 351 - 53.
Goppelt-Struebe M. Stroebel M. Hoppe J. 1996 Regulation of platelet-derived growth factor isoform-mediated expression of prostaglandin G/H synthase in mesangial cells.50 71 78 - 54.
Han C. Michalopoulos G. K. Wu T. 2006 Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells.207 261 270 - 55.
Hanif R. Pittas A. Feng Y. Koutsos M. I. Qiao L. Staiano-Coico L. Shiff S. I. Rigas B. 1996 Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway.52 237 245 - 56.
Hao C. M. Komhoff M. Guan Y. Redha R. MD Breyer 1999 Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival. 277, F352 F359. - 57.
Harris RC, Breyer MD 2001 Physiological regulation of cyclooxygenase-2 in the kidney. 281, F1 11 - 58.
Harris R. C. Mc Kanna J. A. Akai Y. Jacobson H. R. Du Bois. MD Breyer 1994 Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.94 2504 2510 - 59.
Hartner A. Pahl A. Brune K. Goppelt-Struebe M. 2000 Upregulation of cyclooxygenase-1 and the PGE2 receptor EP2 in rat and human mesangioproliferative glomerulonephritis.49 345 354 - 60.
Hebert R. L. Carmosino M. Saito O. Yang G. CA Jackson Qi. Z. Breyer R. M. Natarajan C. Hata A. N. Zhang Y. Guan Y. MD Breyer 2005a Characterization of a rabbit kidney prostaglandin F(2{alpha}) receptor exhibiting G(i)-restricted signaling that inhibits water absorption in the collecting duct.280 35028 35037 - 61.
Hebert R. L. Carmosino M. Saito O. Yang G. CA Jackson Qi. Z. Breyer R. M. Natarajan C. Hata A. N. Zhang Y. Guan Y. MD Breyer 2005b Characterization of a rabbit kidney prostaglandin F(2{alpha}) receptor exhibiting G(i)-restricted signaling that inhibits water absorption in the collecting duct.280 35028 35037 - 62.
Helliwell RJ, Adams LF, Mitchell MD 2004 Prostaglandin synthases: recent developments and a novel hypothesis.70 101 113 - 63.
Hirabayashi T. Murayama T. Shimizu T. 2004 Regulatory mechanism and physiological role of cytosolic phospholipase A2.27 1168 1173 - 64.
Hirahashi J. Takayanagi A. Hishikawa K. Takase O. Chikaraishi A. Hayashi M. Shimizu N. Saruta T. 2000 Overexpression of truncated I kappa B alpha potentiates TNF-alpha-induced apoptosis in mesangial cells.57 959 968 - 65.
Hirose S. Yamamoto T. Feng L. Yaoita E. Kawasaki K. Goto S. Fujinaka H. Wilson C. B. Arakawa M. Kihara I. 1998 Expression and localization of cyclooxygenase isoforms and cytosolic phospholipase A2 in anti-Thy-1 glomerulonephritis.9 408 416 - 66.
Hsu A. L. Ching T. T. DS Wang song. X. Rangnekar V. M. Chen C. S. 2000 The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2.275 11397 11403 - 67.
Imano E. Kanda T. Nakatani Y. Nishida T. Arai K. Motomura M. Kajimoto Y. Yamasaki Y. Hori M. 1998 Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy.21 2135 2139 - 68.
Imig JD, Breyer MD, Breyer RM 2002 Contribution of prostaglandin EP(2) receptors to renal microvascular reactivity in mice. 283, F415 F422. - 69.
Inoue H. Tanabe T. 1997 Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene in vascular endothelial cells.407 139 144 - 70.
Inoue H. Tanabe T. 1998 Transcriptional role of the nuclear factor kappa B site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in U937 cells.244 143 148 - 71.
Ishaque A. MJ Dunn Sorokin. A. 2003 Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells.278 10629 10640 - 72.
Ishibashi R. Tanaka I. Kotani M. Muro S. Goto M. Sugawara A. Mukoyama M. Sugimoto Y. Ichikawa A. Narumiya S. Nakao K. 1999 Roles of prostaglandin E receptors in mesangial cells under high-glucose conditions.56 589 600 - 73.
Iyer R. S. Ghosh S. Salomon R. G. 1989 Levuglandin E2 crosslinks proteins.37 471 480 - 74.
Jaimes E. A. MS Zhou Pearse. D. D. Puzis L. Raij L. 2008 Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species. 294, F385 F392. - 75.
Jang B. C. Sanchez T. Schaefers H. J. Trifan O. C. Liu C. H. Creminon C. Huang C. K. Hla T. 2000 Serum withdrawal-induced post-transcriptional stabilization of cyclooxygenase-2 mRNA in MDA-MB-231 mammary carcinoma cells requires the activity of the38 stress-activated protein kinase. 275, 39507-39515. - 76.
Jania L. A. Chandrasekharan S. Backlund M. G. Foley N. A. Snouwaert J. Wang I. M. Clark P. Audoly L. P. Koller B. H. 2009 Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis.88 73 81 - 77.
Jefferson JA, Johnson RJ 1999 Experimental mesangial proliferative glomerulonephritis (the anti-Thy-1.1 model).12 297 307 - 78.
Jendrossek V. Handrick R. 2003 Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitisers.3 343 353 - 79.
Jensen B. L. Stubbe J. Hansen P. B. Andreasen D. Skott O. 2001 Localization of prostaglandin E(2) EP2 and EP4 receptors in the rat kidney. 280, F1001 F1009. - 80.
Jia Z. Guo X. Zhang H. Wang M. H. Dong Z. Yang T. 2008 Microsomal prostaglandin synthase-1-derived prostaglandin E2 protects against angiotensin II-induced hypertension via inhibition of oxidative stress.52 952 959 - 81.
Jia Z. Wang N. Aoyagi T. Wang H. Liu H. Yang T. 2011 Amelioration of cisplatin nephrotoxicity by genetic or pharmacologic blockade of prostaglandin synthesis.79 77 88 - 82.
Johnstone RW, Ruefli AA, Smyth MJ 2000a Multiple physiological functions for multidrug transporter P-glycoprotein?25 1 6 - 83.
Johnstone RW, Ruefli AA, Tainton KM, Smyth MJ 2000b A role for P-glycoprotein in regulating cell death.38 1 11 - 84.
Kawanishi S. Hiraku Y. 2004 Amplification of anticancer drug-induced DNA damage and apoptosis by DNA-binding compounds.4 415 419 - 85.
Kelefiotis D. BA Bresnahan Stratidakis. I. Lianos E. A. 1995 Eicosanoid-induced growth and signaling events in rat glomerular mesangial cells.49 269 283 - 86.
Kester M. Coroneos E. Thomas P. J. MJ Dunn 1994 Endothelin stimulates prostaglandin endoperoxide synthase-2 mRNA expression and protein synthesis through a tyrosine kinase-signaling pathway in rat mesangial cells.269 22574 22580 - 87.
Khan KN, Stanfield KM, Harris RK, Baron DA 2001 Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy.23 321 330 - 88.
Khanna R. 2011 Clinical presentation & management of glomerular diseases: hematuria, nephritic & nephrotic syndrome.108 33 36 - 89.
Kim SF, Huri DA, Snyder SH 2005 Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2.310 1966 1970 - 90.
Kim WJ, Kim JH, Jang SK 2007 Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4A.26 5020 5032 - 91.
Kliewer S. A. Umesono K. Noonan D. J. Heyman R. A. Evans R. M. 1992 Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors.358 771 774 - 92.
Kobayashi T. Narumiya S. 2002 Function of prostanoid receptors: studies on knockout mice. 68-69, 557-573. - 93.
Kosaka T. Miyata A. Ihara H. Hara S. Sugimoto T. Takeda O. Takahashi E. Tanabe T. 1994 Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2.221 889 897 - 94.
Kudo I. Murakami M. 2005 Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis.38 633 638 - 95.
Kurogi Y. 2003 Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease.23 15 31 - 96.
Leak TS, Perlegas PS, Smith SG, Keene KL, Hicks PJ, Langefeld CD, Mychaleckyj JC, Rich SS, Kirk JK, Freedman BI, Bowden DW, Sale MM 2009 Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans.73 152 159 - 97.
Lecomte M. Lecocq R. Dumont J. E. Boeynaems J. M. 1990 Covalent binding of arachidonic acid metabolites to human platelet proteins. Identification of prostaglandin H synthase as one of the modified substrates.265 5178 5187 - 98.
Lianos EA 1992 Eicosanoids in immune-mediated renal injury.12 441 453 - 99.
Lianos EA, Andres GA, Dunn MJ 1983 Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.72 1439 1448 - 100.
Lin MT, Lee RC, Yang PC, Ho FM, Kuo ML 2001 Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/Akt pathway.276 48997 49002 - 101.
Lin WN, Lin CC, Cheng HY, Yang CM 2011 Regulation of COX-2 and cPLA(2) gene expression by LPS through the RNA-binding protein HuR: involvement of NADPH oxidase, ROS and MAPKs. Br.J.Pharmacol. - 102.
Liu X. H. Yao S. Kirschenbaum A. Levine A. C. 1998 NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells.58 4245 4249 - 103.
Lovgren A. K. Kovarova M. Koller B. H. 2007 cPGES/23 is required for glucocorticoid receptor function and embryonic growth but not prostaglandin E2 synthesis. 27, 4416-4430. - 104.
Ma Marcantoni L. J. Linton C. Fazio M. F. Fogo S. A. B. 2001 Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats.59 1899 1910 - 105.
Maeda A. Horikoshi S. Gohda T. Tsuge T. Maeda K. Tomino Y. 2005 Pioglitazone attenuates TGF-beta(1)-induction of fibronectin synthesis and its splicing variant in human mesangial cells via activation of peroxisome proliferator-activated receptor (PPAR)gamma.29 422 428 - 106.
Mahadevan P. Larkins R. G. Fraser J. R. ME Dunlop 1996 Effect of prostaglandin E2 and hyaluronan on mesangial cell proliferation. A potential contribution to glomerular hypercellularity in diabetes.45 44 50 - 107.
Mangat H. Peterson L. N. Burns K. D. 1997 Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors.100 1941 1950 - 108.
Markan S. Kohli H. S. Sud K. Ahuja M. Ahluwalia T. S. Sakhuja V. Khullar M. 2008 Oxidative stress in primary glomerular diseases: a comparative study.311 105 110 - 109.
Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA 1999 Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition.274 22903 22906 - 110.
Matlhagela K. Taub M. 2006 Involvement of EP1 and EP2 receptors in the regulation of the Na,K-ATPase by prostaglandins in MDCK cells.79 101 113 - 111.
Mbonye U. R. Yuan C. CE Harris Sidhu. R. S. Song I. Arakawa T. Smith W. L. 2008 Two distinct pathways for cyclooxygenase-2 protein degradation.283 8611 8623 - 112.
Mc Ginty A. Foschi M. Chang Y. W. Han J. MJ Dunn Sorokin. A. 2000 Induction of prostaglandin endoperoxide synthase 2 by mitogen-activated protein kinase cascades. 352 Pt2 419 424 - 113.
McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM, Almoosa KF, Liggett SB 2006 Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex.116 1400 1409 - 114.
Mene P. Dubyak G. R. Scarpa A. MJ Dunn 1991 Regulation of cytosolic pH of cultured mesangial cells by prostaglandin F2 alpha and thromboxane A2. 260, C159 C166. - 115.
Menter DG, Schilsky RL, DuBois RN 2010 Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward.16 1384 1390 - 116.
Milatovic D. Montine T. J. Aschner M. 2011 Prostanoid signaling: Dual role for prostaglandin E(2) in neurotoxicity.32 312 319 - 117.
Miller B. Patel V. A. Sorokin A. 2006 Cyclooxygenase-2 Rescues Rat Mesangial Cells from Apoptosis Induced by Adriamycin via Upregulation of Multidrug Resistance Protein 1 (P-Glycoprotein).17 977 985 - 118.
Miller SB 2006 Prostaglandins in health and disease: an overview.36 37 49 - 119.
Moore BC, Simmons DL 2000 COX-2 inhibition, apoptosis, and chemoprevention by nonsteroidal anti-inflammatory drugs.7 1131 1144 - 120.
Morath R. Klein T. Seyberth H. W. Nusing R. M. 1999 Immunolocalization of the four prostaglandin E2 receptor proteins EP1, EP2, EP3, and EP4 in human kidney.10 1851 1860 - 121.
Naraba H. Yokoyama C. Tago N. Murakami M. Kudo I. Fueki M. Oh-Ishi S. Tanabe T. 2002 Transcriptional regulation of the membrane-associated prostaglandin E2 synthase gene. Essential role of the transcription factor Egr-1.277 28601 28608 - 122.
Narumiya S. Sugimoto Y. Ushikubi F. 1999 Prostanoid receptors: structures, properties, and functions.79 1193 1226 - 123.
Nasrallah R. Clark J. Hebert R. L. 2007 Prostaglandins in the kidney: developments since Y2K.113 297 311 - 124.
Nasrallah R. Landry A. Singh S. Sklepowicz M. Hebert R. L. 2003 Increased expression of cyclooxygenase-1 and-2 in the diabetic rat renal medulla. 285, F1068 F1077. - 125.
Neuhofer W. Steinert D. Fraek M. L. Beck F. X. 2007 Prostaglandin E2 stimulates expression of osmoprotective genes in MDCK cells and promotes survival under hypertonic conditions.583 287 297 - 126.
Nicholas S. B. Kawano Y. Wakino S. Collins A. R. Hsueh W. A. 2001 Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells.37 722 727 - 127.
Nomura T. Chang H. Y. Lu R. Hankin J. Murphy R. C. Schuster V. L. 2005 Prostaglandin signaling in the renal collecting duct: release, reuptake, and oxidation in the same cell.280 28424 28429 - 128.
Nusing R. M. Treude A. Weissenberger C. Jensen B. Bek M. Wagner C. Narumiya S. Seyberth H. W. 2005 Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome.16 2354 2362 - 129.
Padilla J. Kaur K. Harris S. G. Phipps R. P. 2000 PPAR-gamma-mediated regulation of normal and malignant B lineage cells.905 97 109 - 130.
Panzer U. Zahner G. Wienberg U. Steinmetz O. M. Peters A. Turner J. E. Paust H. J. Wolf G. Stahl R. A. Schneider A. 2008 deoxy-Delta12 14 prostaglandin J2 inhibits INF-gamma-induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells. 23, 3776-3785. - 131.
Parfenova H. Balabanova L. Leffler C. W. 1998 Posttranslational regulation of cyclooxygenase by tyrosine phosphorylation in cerebral endothelial cells. 274, C72 C81. - 132.
Patel V. A. MJ Dunn Sorokin. A. 2002 Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2.277 38915 38920 - 133.
Pezzolesi M. G. Katavetin P. Kure M. Poznik G. D. Skupien J. Mychaleckyj J. C. Rich S. S. Warram J. H. AS Krolewski 2009 Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy.58 2698 2702 - 134.
Rahal S. Mc Veigh L. I. Zhang Y. Guan Y. MD Breyer Kennedy. C. R. 2006 Increased severity of renal impairment in nephritic mice lacking the EP1 receptor.84 877 885 - 135.
Ricciotti E. Fitzgerald G. A. 2011 Prostaglandins and inflammation.31 986 1000 - 136.
Ricote M. Li A. C. Willson T. M. Kelly C. J. Glass C. K. 1998 The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.391 79 82 - 137.
Riedl K. Krysan K. Pold M. Dalwadi H. Heuze-Vourc’h N. Dohadwala M. Liu M. Cui X. Figlin R. Mao J. T. Strieter R. Sharma S. Dubinett S. M. 2004 Multifaceted roles of cyclooxygenase-2 in lung cancer.7 169 184 - 138.
Rizzo G. Fiorucci S. 2006 PPARs and other nuclear receptors in inflammation.6 421 427 - 139.
Saha D. Datta P. K. Sheng H. JD Morrow Wada. M. Moses H. L. Beauchamp R. D. 1999 Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells.1 508 517 - 140.
Saito O. Guan Y. Qi Z. Davis L. S. Komhoff M. Sugimoto Y. Narumiya S. Breyer R. M. MD Breyer 2003 Expression of the prostaglandin F receptor (FP) gene along the mouse genitourinary tract. 284, F1164 F1170. - 141.
Salomon RG, Miller DB 1985 Levuglandins: isolation, characterization, and total synthesis of new secoprostanoid products from prostaglandin endoperoxides.15 323 326 - 142.
Satoh T. Moroi R. Aritake K. Urade Y. Kanai Y. Sumi K. Yokozeki H. Hirai H. Nagata K. Hara T. Utsuyama M. Hirokawa K. Sugamura K. Nishioka K. Nakamura M. 2006 Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor.177 2621 2629 - 143.
Savill J. 1999 Regulation of glomerular cell number by apoptosis.56 1216 1222 - 144.
Scher JU, Pillinger MH 2005 d-PGJ2: the anti-inflammatory prostaglandin?114 100 109 - 145.
Schneider A. Stahl R. A. 1998 Cyclooxygenase-2 (COX-2) and the kidney: current status and potential perspectives.13 10 12 - 146.
Schuster VL 2002 Prostaglandin transport. 68-69, 633-647. - 147.
Schweda F. Klar J. Narumiya S. Nusing R. M. Kurtz A. 2004 Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys. 287, F427 F433. - 148.
Seibert K. Masferrer J. L. Needleman P. Salvemini D. 1996 Pharmacological manipulation of cyclo-oxygenase-2 in the inflamed hydronephrotic kidney.117 1016 1020 - 149.
Shimazaki A. Kawamura Y. Kanazawa A. Sekine A. Saito S. Tsunoda T. Koya D. Babazono T. Tanaka Y. Matsuda M. Kawai K. Iiizumi T. Imanishi M. Shinosaki T. Yanagimoto T. Ikeda M. Omachi S. Kashiwagi A. Kaku K. Iwamoto Y. Kawamori R. Kikkawa R. Nakajima M. Nakamura Y. Maeda S. 2005 Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy.54 1171 1178 - 150.
Shimazaki A. Tanaka Y. Shinosaki T. Ikeda M. Watada H. Hirose T. Kawamori R. Maeda S. 2006 ELMO1 increases expression of extracellular matrix proteins and inhibits cell adhesion to ECMs.70 1769 1776 - 151.
Shimizu T. Wolfe L. S. 1990 Arachidonic acid cascade and signal transduction.55 1 15 - 152.
Shiraya K. Hirata T. Hatano R. Nagamori S. Wiriyasermkul P. Jutabha P. Matsubara M. Muto S. Tanaka H. Asano S. Anzai N. Endou H. Yamada A. Sakurai H. Kanai Y. 2010 A novel transporter of SLC22 family specifically transports prostaglandins and co-localizes with 15-hydroxyprostaglandin dehydrogenase in renal proximal tubules.285 22141 22151 - 153.
Silva PJ, Fernandes PA, Ramos MJ 2007 A theoretical study of radical-only and combined radical/carbocationic mechanisms of arachidonic acid cyclooxygenation by prostaglandin H synthase.110 345 351 - 154.
Six DA, Dennis EA 2000 The expanding superfamily of phospholipase A(2) enzymes: classification and characterization.1488 1 19 - 155.
Smith WL, DeWitt DL, Garavito RM 2000 Cyclooxygenases: structural, cellular, and molecular biology.69 145 182 - 156.
Sorokin A. 2004 Cyclooxygenase-2: potential role in regulation of drug efflux and multidrug resistance phenotype.10 647 657 - 157.
Spencer A. G. Thuresson E. Otto J. C. Song I. Smith T. De Witt D. L. Garavito R. M. Smith W. L. 1999 The membrane binding domains of prostaglandin endoperoxide H synthases 1 and 2. Peptide mapping and mutational analysis.274 32936 32942 - 158.
Steinert D. Kuper C. Bartels H. Beck F. X. Neuhofer W. 2009 PGE2 potentiates tonicity-induced COX-2 expression in renal medullary cells in a positive feedback loop involving EP2 cAMP-PKA signaling. 296, C75-C87. - 159.
Stitt-Cavanagh E. M. Faour W. H. Takami K. Carter A. Vanderhyden B. Guan Y. Schneider A. MD Breyer Kennedy. C. R. 2010 A maladaptive role for EP4 receptors in podocytes.21 1678 1690 - 160.
Stock J. L. Shinjo K. Burkhardt J. Roach M. Taniguchi K. Ishikawa T. Kim H. S. Flannery P. J. Coffman T. M. JD Mc Neish Audoly. L. P. 2001 The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure.107 325 331 - 161.
Subbaramaiah K. Altorki N. Chung W. J. Mestre J. R. Sampat A. Dannenberg A. J. 1999 Inhibition of cyclooxygenase-2 gene expression by53 274, 10911-10915. - 162.
Subbaramaiah K. Marmo T. P. Dixon D. A. Dannenberg A. J. 2003 Regulation of cyclooxgenase-2 mRNA stability by taxanes: evidence for involvement of38 MAPKAPK-2, and HuR. 278, 37637-37647. - 163.
Subbaramaiah K. Yoshimatsu K. Scherl E. Das K. M. Glazier K. D. Golijanin D. Soslow R. A. Tanabe T. Naraba H. Dannenberg A. J. 2004 Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1.279 12647 12658 - 164.
Subbaramaiah K. Zakim D. Weksler B. B. Dannenberg A. J. 1997 Inhibition of cyclooxygenase: a novel approach to cancer prevention.216 201 210 - 165.
Sugawara A. Uruno A. Kudo M. Matsuda K. Yang C. W. Ito S. 2010 Effects of PPARgamma on hypertension, atherosclerosis, and chronic kidney disease.57 847 852 - 166.
Sugimoto Y. Narumiya S. 2007 Prostaglandin E receptors.282 11613 11617 - 167.
Sun L. K. Beck-Schimmer B. Oertli B. Wuthrich R. P. 2001 Hyaluronan-induced cyclooxygenase-2 expression promotes thromboxane A2 production by renal cells.59 190 196 - 168.
Takahashi N. Breitman T. R. 1992 Covalent modification of proteins by ligands of steroid hormone receptors.89 10807 10811 - 169.
Tegeder I. Pfeilschifter J. Geisslinger G. 2001 Cyclooxygenase-independent actions of cyclooxygenase inhibitors.15 2057 2072 - 170.
MJ Thun Henley. S. J. Patrono C. 2002 Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues.94 252 266 - 171.
Thuresson E. D. Lakkides K. M. Rieke C. J. Sun Y. BA Wingerd Micielli. R. Mulichak A. M. Malkowski M. G. Garavito R. M. Smith W. L. 2001 Prostaglandin endoperoxide H synthase-1: the functions of cyclooxygenase active site residues in the binding, positioning, and oxygenation of arachidonic acid.276 10347 10357 - 172.
Tian J. Kim S. F. Hester L. Snyder S. H. 2008 S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity.105 10537 10540 - 173.
Tomasoni S. Noris M. Zappella S. Gotti E. Casiraghi F. Bonazzola S. Benigni A. Remuzzi G. 1998 Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.9 1202 1212 - 174.
Tsatsanis C. Androulidaki A. Venihaki M. Margioris A. N. 2006 Signalling networks regulating cyclooxygenase-2.38 1654 1661 - 175.
Tsujii M. Du Bois. RN 1995 Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2.83 493 501 - 176.
Turini ME, DuBois RN 2002 Cyclooxygenase-2: a therapeutic target.53 35 57 - 177.
Uozumi N. Shimizu T. 2002 Roles for cytosolic phospholipase A2alpha as revealed by gene-targeted mice. 68-69, 59-69. - 178.
Vezza R. Habib A. Li H. Lawson J. A. Fitzgerald G. A. 1996 Regulation of cyclooxygenases by protein kinase C. Evidence against the importance of direct enzyme phosphorylation.271 30028 30033 - 179.
von Euler US 1936 On the specific vaso-dilating and plain muscle stimulating substances from accessory genital glands in man and certain animals (prostaglandin and vesiglandin).88 213 234 - 180.
von Knethen. A. Brune B. 1997 Cyclooxygenase-2: an essential regulator of NO-mediated apoptosis.11 887 895 - 181.
Wada M. Saunders T. L. Morrow J. Milne G. L. Walker K. P. Dey S. K. Brock T. G. Opp M. R. Aronoff D. M. Smith W. L. 2009 Two pathways for cyclooxygenase-2 protein degradation in vivo.284 30742 30753 - 182.
Wang J. L. Cheng H. F. Shappell S. Harris R. C. 2000 A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats.57 2334 2342 - 183.
Wang S. Meng F. Xu J. Gu Y. 2009 Effects of lipids on ENaC activity in cultured mouse cortical collecting duct cells.227 77 85 - 184.
Widmann C. Gibson S. Jarpe M. B. Johnson G. L. 1999 Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human.79 143 180 - 185.
Wilson AG, Kung HC, Anderson MW, Eling TE 1979 Covalent binding of intermediates formed during the metabolism of arachidonic acid by human platelet subcellular fractions.18 409 422 - 186.
Wilson T. W. Alonso-Galicia M. Roman R. J. 1998 Effects of lipid-lowering agents in the Dahl salt-sensitive rat.31 225 231 - 187.
Wong S. L. Leung F. P. Lau C. W. Au C. L. Yung L. M. Yao X. Chen Z. Y. Vanhoutte P. M. Gollasch M. Huang Y. 2009 Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging.104 228 235 - 188.
Yamamoto S. Yamamoto K. Kurobe H. Yamashita R. Yamaguchi H. Ueda N. 1998 Transcriptional regulation of fatty acid cyclooxygenases-1 and-2.20 17 22 - 189.
Yamamoto T. Wilson C. B. 1987 Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat.32 514 525 - 190.
Yang C. Sorokin A. 2011 Upregulation of fibronectin expression by COX-2 is mediated by interaction with ELMO1.23 99 104 - 191.
Yuan C. Rieke C. J. Rimon G. BA Wingerd Smith. W. L. 2006 Partnering between monomers of cyclooxygenase-2 homodimers.103 6142 6147 - 192.
Zager RA 2001 P glycoprotein-mediated cholesterol cycling determines proximal tubular cell viability.60 944 956 - 193.
Zaza G. Granata S. Sallustio F. Grandaliano G. Schena F. P. 2010 Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients.159 268 280 - 194.
Zhang A. Dong Z. Yang T. 2006 Prostaglandin D2 inhibits TGF-beta1 induced epithelial-to-mesenchymal transition in MDCK cells. 291, F1332-F1342. - 195.
Zheng F. Fornoni A. Elliot S. J. Guan Y. MD Breyer Striker. L. J. Striker G. E. 2002 Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation. 282, F639 F648.