Eicosanoids and Renal Function

Perhaps nothing underscores the special relationship between the kidney and the eicosanoids better than the profound clinical effects non-steroidal anti-inflammatory drugs (NSAIDS) have on kidney function. NSAIDs are widely used to treat pain and inflammatory diseases, and work by blocking the enzymatic synthesis of prostaglandins, a type of eicosanoid, from arachidonic acid. However, chronic NSAID use is often complicated by major side effects, including renal sodium retention, resulting in edema, hypertension, and congestive heart failure. Conversely, in the sodium depleted state, NSAIDs can reduce renal blood flow, glomerular filtration rate, and cause acute renal failure. These observations underscore the critical role cyclooxygenase-derived arachidonic acid metabolites play in maintaining normal kidney function – particularly in the setting of physiological stress.

Perhaps nothing underscores the special relationship between the kidney and the eicosanoids better than the profound clinical effects non-steroidal anti-inflammatory drugs (NSAIDS) have on kidney function. NSAIDs are widely used to treat pain and inflammatory diseases, and work by blocking the enzymatic synthesis of prostaglandins, a type of eicosanoid, from arachidonic acid. However, chronic NSAID use is often complicated by major side effects, including renal sodium retention, resulting in edema, hypertension, and congestive heart failure. Conversely, in the sodium depleted state, NSAIDs can reduce renal blood flow, glomerular filtration rate, and cause acute renal failure. These observations underscore the critical role cyclooxygenase-derived arachidonic acid metabolites play in maintaining normal kidney function – particularly in the setting of physiological stress.

Cellular Origin of Eicosanoids

Eicosanoids are a family of biologically active, oxygenated metabolites derived from arachidonic acid (AA). AA is comprised of 20 carbon atoms configured as a polyunsaturated fatty acid chain with four double bonds (C20:4). Mammals lack the enzymatic machinery to synthesize AA de novo , instead it must be formed from dietary linoleic acid (C18:2) by addition of two carbons and further desaturation. Essential fatty acid (EFA) deficiency occurs in the absence of dietary linoleic and other fatty acid AA precursors, depleting the hormone-responsive pool of AA metabolite products. Of the approximate 10 gm of linoleic acid ingested per day, only about 1 mg/day is eliminated as end products of AA metabolism. Following its formation, AA is esterified into cell membrane phospholipids, principally at the 2 position of the phosphatidylinositol fraction (i.e., sn-2 esterified AA). This source comprises the major hormone-sensitive pool of AA that is susceptible to release by phospholipases.

Phospholipase-Mediated Arachidonic Acid Release

Multiple stimuli lead to release of membrane-phospholipid esterified AA via activation of cellular phospholipases, principally phospholipase A2s (PLA 2 ). This cleavage step is rate-limiting in the production of arachidonate metabolites. Activation of phospholipase C or PLD, on the other hand, releases AA via the sequential action of the phospholipase C-mediated production of diacylglycerol (DAG), with subsequent release of AA from DAG by DAG lipase. The physiological significance of AA release by these other phospholipases remains uncertain since, at least in the setting of inflammation, phospholipase A 2 action appears to be essential for the generation of biologically active AA metabolites. Cellular levels of free arachidonic acid available for eicosanoid production are primarily controlled by phospholipase A2 (PLA2). So far, more than 30 enzymes with PLA 2 activity have been identified, and have been classified into four groups: secretory PLA 2 (sPLA2); cytosolic PLA2 (cPLA2); calcium-independent PLA2 (iPLA2); and PAF acetylhydrolases (PAF-AH). The activity of cPLA2 is regulated by diverse cell membrane receptors, including the EGF receptor, and transmembrane guanine-nucleotide protein coupled (GPCRs) including adrenergic receptors, angiotensin II receptors, and purinergic receptors. These receptors activate guanine nucleotide-binding (G) proteins, leading to PLA 2 -mediated release of AA from membrane phospholipids. Alternatively, these receptors may activate cPLA 2 via mitogen-activated protein kinases (MAPK), protein kinase C (PKC), and Ca 2+ -calmodulin-dependent kinases.

Ambient physical conditions in the kidney including hypoxia, oxidative stress, and mechanical stretch can also activate PLA 2 activity. Dysregulated renal PLA 2 activity with attendant change in AA release results in altered substrate availability for the production of downstream metabolic products. This activation is believed to contribute to pathologic processes including acute kidney injury, diabetic nephropathy, and inflammatory glomerulonephritis. Some snake and bee venoms are imbued with high levels of secretory PLA 2 activity and, in part through this activity, can induce acute renal failure . A role for secretory PLA 2 in the pathogenesis of acute ischemic-reperfusion renal injury has also been supported by studies showing that sPLA 2 neutralizing antibodies protect rats from this form of injury.

Phospholipase A2 Receptors

Recently, an important role for a transmembrane cell surface secretory PLA 2 receptor (PLA 2 R) has been recognized in the pathogenesis of human idiopathic membranous nephropathy. Auto-antibodies to PLA 2 R are detected in ~70% of cases of human idiopathic membranous nephropathy. The antigen appears to be selectively expressed in podocytes ; however, the mechanism by which the auto-antibodies induce proteinuria and how these auto-antibodies arise remains to be determined. PLA 2 R is a type I transmembrane receptor and one of four mammalian members of the mannose-receptor family. PLA 2 R was initially identified as a binding protein for secreted phospholipase A 2 (PLA 2 ) that now has been expanded to a PLA 2 R family that exhibit different affinities for the secreted PLA 2 . New studies suggest these receptors could play additional transmembrane signaling roles, and may promote terminal cell differentiation and mitotic arrest.

Arachidonic Acid Metabolism

Following its release from membrane phospholipids, AA is usually rapidly re-esterified into the membrane or avidly bound by intracellular proteins, becoming unavailable for further metabolism. Should AA escape re-esterification and protein binding, it may be metabolized through one of three major enzymatic transformations, the common result of which is the incorporation of oxygen atoms at various sites of the fatty acid backbone, with accompanying changes in its molecular structure (such as ring formation). This results in the formation of biologically active molecules, collectively referred to as “eicosanoids.” The specific nature of the products generated is a function of the initial stimuli for AA release, as well as the metabolic enzymes available, as determined by the cell type involved.

Enyzmes capable of mediating AA metabolism through all three known pathways are present in the kidney, including cyclooxygenases 1 and 2, lipoxygenases, and cytochrome P450s ( Figure 17.1 ). Cyclooxygenase (COX, also called Prostaglandin H2 synthase or PGHS)-mediated AA metabolism comprises the first committed step in the formation of prostaglandins (PGs), prostacyclin, and thromboxane. The lipoxygenase pathway mediates the formation of mono-, di-, and trihydroxyeicosatetraenoic acids (HETEs), leukotrienes (LTs), and lipoxins (LXs), and the cytochrome P450-dependent oxygenation of AA mediates the formation of epoxyeicosatrienoic acids (EETs), their corresponding diols, HETEs, and monooxygenated AA derivatives. Fish oil diets, rich in n-3 polyunsaturated fatty acids ( n-3 fatty acids are those in which the double bond is three carbons from the terminal, i.e., n carbon, that is furthest from the carboxy-group atom, AA is thus an n-6 fatty acid) interfere with metabolism via all three pathways by competing with AA oxygenation, resulting in the formation of biologically inactive end-products. Interference with the production of pro-inflammatory lipids has been hypothesized to underlie the beneficial effects of fish-oil in IgA nephropathy, membranous nephropathy, and other cardiovascular diseases.

Figure 17.1

Prostaglandin synthesis and the family of G-protein coupled receptors that mediate their functional effects.

(With permission from Yuhki et al. .)

Cyclooxygenase Derived Prostanoids

Prostanoids, including the prostaglandins PGE 2 , PGF , and PGD 2 , as well as the non-prostaglandin molecules thromboxane A 2 (TxA2) and prostacyclin (PGI 2 ), are derived from arachidonic acid via its di-oxygenation by cyclooxygenases 1 and 2 (COX1 and COX2). Cyclooxygenases exist as homodimers that are physically associated with, but do not pass through, the intracellular endoplasmic reticular membrane. Cyclooxygenases mediate a two-step reaction, initially converting free arachidonic acid to the unstable intermediate PGG 2 via a bis -oxygenase activity. PGG 2 is converted to PGH 2 via the peroxidase activity of COX. PGH 2 is subsequently metabolized to more stable primary biologically active prostanoids PGE 2 , PGF , PGD 2 , PGI 2 , and TxA 2 by distinct enzymatic prostanoid synthases. These prostanoids exit the cell through uncharacterized mechanisms, where they exert paracrine or autocrine activity on specific and distinct cell surface G-protein coupled receptor(s). There is also less definitive evidence that prostanoids may provide physiologically relevant ligands for nuclear hormone receptors, including peroxisome proliferator activated receptors.

Two isoforms of COX have been identified, designated COX1 and COX2. Based on transcriptional elements in its 5′ upstream sequence, COX1 is believed to serve a constitutive housekeeping role, responsible for maintaining basic physiological function such as cytoprotection of the gastric mucosa, and control of platelet aggregation. Conversely, COX2 upstream promoter region has NF-κB, NFAT, and its expression is potently induced by inflammatory mediators and mitogens, consistent with its role in pathophysiologic processes including angiogenesis, inflammation, and tumorigenesis.

The major phenotype of COX2 knockout mice is renal dysgenesis, underscoring the special role COX2 plays in the kidney. This defect is characterized by a structurally normal medulla, but hypotrophic renal cortical development with small glomerular size, due to a defect occurring relatively late in partuition. The mechanism is undetermined, but may be related to the particular expression pattern of COX2 in the kidney since normally it is focally expressed adjacent to the glomerulus in the macula densa and the surrounding thick ascending limb cells. As in other organs, the housekeeping gene is COX1, which is also constitutively expressed at high levels in the kidney but in cellular compartments distinct from COX2, especially in the collecting duct and glomerular parietal epithelium. Low levels of COX1 are also detected in medullary interstitial cells, but these cells are also uniquely characterized by high endogenous levels of COX2.

Clinical pharmacologic studies are also consistent with a critical role of COX2 for maintaining cardiovascular homeostasis and normal renal function. Indeed, most of the clinically observed side effects associated with the use of non-selective NSAIDs, including edema, hypertension, increased congestive heart failure, hyperkalemia, and acute renal failure, have also been observed with COX2 selective inhibitors. COX2-dependent PGE 2 production is inversely related to luminal chloride concentration delivered to the macula densa, so that in volume depleted states high PGE 2 production rates may exert a vasodilator effect on the afferent arteriole, contributing to maintenance of glomerular blood flow. Impairment of renal function is presumed due to loss of specific prostanoids, derived from the metabolism of the common cyclooxygenase product PGH 2 .

Prostanoid Function

Once formed, the COX-derived arachidonate metabolite PGH 2 is further metabolized by prostanoid synthases into at least five primary biologically active prostanoids. Prostanoid synthases include PGE 2 synthase (PGES), prostacyclin synthase (PGIS), PGD synthase (PGDS), PGF synthase (PGFS), and thromboxane synthase, responsible for PGE2, PGI2, PGD2, PGF2α, and TxA2 biosynthesis respectively.

Most prostanoids are short lived, being highly susceptible to enzymatic inactivation, thereby limiting their effect to the immediate vicinity of their synthesis. The paracrine and autocrine biologic effects of COX-derived prostanoids are diverse and complex, depending on which prostanoid is produced and which receptor is available. Thus, the effects of prostanoids on kidney function rely on distinct enzymatic machinery that couples phospholipase and COX to specific prostanoid synthase in specific cells, yielding a specific prostanoid which acts locally through specific G-protein coupled receptors, exerting its particular effect.

At steady-state PGE 2 is the most abundant prostanoid in the mouse kidney, followed by PGI 2 , PGF , and TxA 2 . Under basal conditions, both COX1 and COX2 pathways are responsible for the biosynthesis of these prostanoids. Similarly, PGE2 is the most abundant prostanoid in human urine, and under basal, non-stressed conditions is produced by both COX1 and COX. In contrast, COX2 primarily contributes to angiotensin II-induced PGE 2 and PGI2 generation in the kidney, and under conditions of low-sodium diet in humans. The intrarenal cellular sites where COX1 and COX2 prostanoids are synthesized remain to be fully defined.

Following their synthesis, these prostanoids become available to exert their biological effects via a diverse family of membrane spanning G-protein coupled prostanoid receptors. These include the DP, EP, FP, IP, and TP receptors, each of which is selectively activated by a specific ligand – PGD 2 , PGE 2 , PGF , PGI 2 or TXA 2 , respectively. PGE2 receptors, designated EP receptors, are unique in that they are encoded by four distinct genes encoding the proteins for EP1, EP2, EP3, and EP4 receptors. Each prostanoid receptor activates a distinct G-protein coupled signaling pathway. The IP, DP1, EP2, and EP4 receptors are coupled to the stimulatory G-protein (Gs) and signal by increasing intracellular cAMP levels, whereas the TP, FP, and EP1 receptors induce calcium mobilization. The FP, DP2, and EP3 receptors can couple to an inhibitory G-protein (Gi) and reduce cAMP synthesis.

Restricted cellular expression of prostanoid receptors provides an important mechanism by which a COX-derived prostanoid can exert differential actions in physiological and pathophysiological processes. In the kidney the EP receptors map to distinct segments of the nephron. Similarly, all four EP receptors have been described in major inflammatory cells including T-lymphocytes, B-lymphocytes, macrophage, and mast cells ; however, whether these receptors are simultaneously expressed in individual cells is uncertain. It has been proposed that activation of different receptors on different cells at different stages of inflammation may account for the pro- or anti-inflammatory action of PGE 2 .

Prostaglandin E2

PGE 2 is synthesized by at least three forms of PGE synthases, including microsomal PGE synthase 1 (mPGES1), microsomal PGE synthase 2 (mPGES2), and cytosolic PGE synthase (cPGES1). The two membrane associated PGE 2 synthases are 33 kDa and 16 kDa enzymes designated mPGES1 and mPGES2, respectively. Microsomal PGES1 displays a higher catalytic activity relative to other PGE synthases and, like COX2, its expression can be induced by cytokines and inflammatory stimuli. In contrast, the expression of cPGES and mPGES2 do not seem to be inducible and may play housekeeping functions.

Genetic disruption confirms that mPGES1 −/− mice exhibit a marked reduction in inflammatory responses compared with mPGES1 +/+ mice, and indicates that mPGES1 is critical for the induction of inflammatory fever. It has been proposed that mPGES1 couples primarily to the inducible COX2 in inflammatory cells. In contrast, intrarenal expression of mPGES1 maps to cells of the collecting duct that primarily express COX1 with lower expression in medullary interstitial cells and macula densa that express COX2 ( Figure 17.2 ). Thus, in the kidney mPGE1 co-localizes with both cyclooxygenase 1 and 2. The renal phenotype of the mPGE1 knockout mouse is relatively subtle, and is characterized by increased blood pressure sensitivity to high-sodium diet and mineralocorticoids, as well as increased vascular reactivity to angiotensin-II, although not all investigators have seen these effects. These results are consistent with a role for mPGES1-derived PGE 2 in buffering physiologic stresses that tend to increase blood pressure. Notably, the kidneys of mPGES1 −/− mice are normal and do not exhibit the renal dysgenesis observed in COX2 −/− mice. Nor do these mice exhibit perinatal death from patent ductus arteriosus observed with the prostaglandin EP4 receptor knockout mouse, suggesting other sources of PGE2 production are sufficient to provide adequate receptor activation. These sources could include cPGES and mPGES2. Both cPGES and mPGES2 are expressed in the kidney ; however, their intrarenal role(s) have not yet been elucidated. In addition, several cytosolic glutathione-S-transferases have the capacity to convert PGH 2 to PGE 2 ; however, their physiologic role in this process remains uncertain.

Figure 17.2

Expression of COX1, COX2, and microsomal prostaglandin E synthase 1 in the kidney.

(With permission from ref. .)

E-Prostanoid Receptors

All four E-Prostanoid receptors (EP receptors) are expressed in the kidney ( Figure 17.3 ). Each exhibits a distinct mRNA expression profile along the nephron. The EP4 receptor predominates in the glomerulus, while the EP3 and EP1 receptors are primarily detected in the thick limb and collecting duct. The EP2 receptor is expressed at lower levels in the renal vaculature and stroma. Each receptor plays a distinct role in these regions, mediating many of the well-defined physiologic actions of PGE 2 that have been identified over the past several decades.

Figure 17.3

Distribution of EP1, 2, 3, 4, and FP receptors in the kidney.

EP 1 Receptor

The EP1 receptor was originally identified pharmacologically via its smooth muscle constrictor activity in guinea pig ileum, and its unique profile of response to a series of prostanoid analogs. The EP1 receptor cDNA has been cloned from numerous species, including human, dog, mouse, rat, and rabbit. The human EP1 receptor cDNA encodes a 402 amino acid polypeptide with a predicted molecular mass of 41,858 kDa. This receptor signals via a mechanism linked to increased cell Ca + , and is accompanied by modest increases in IP 3 generation.

Studies of EP1 receptors have taken advantage of several relatively selective antagonists that block their activation, including SC-19220, SC-53122, and ONO-8130. A significant impetus behind the development of clinically active EP1 receptor antagonists derives from evidence that the EP 1 receptor plays an important role in prostaglandin-mediated pain, and that EP1 receptor antagonists have EP1 properties. These antagonists provide useful tools to study EP 1 receptor physiology in vivo .

The EP1 receptor is highly expressed in the kidney, where it primarily localizes to the collecting duct with an increasing mRNA expression gradient from the cortical to the medullary collecting duct. In the collecting duct, activation of the EP1 receptor inhibits Na + and water reabsorption via a Ca 2+ -coupled mechanism. These results suggest that renal EP 1 receptor activation contributes to PGE 2 -dependent natriuresis by inhibiting Na + transport in the collecting duct. Despite this in vitro demonstration, these natriuretic effects have been difficult to demonstrate in vivo .

Genetic disruption of the EP1 receptor does not lead to a significant impairment of sodium excretion; however, EP1 knockout mice do exhibit increased renin and aldosterone levels, consistent with maintenance of normotension at the expense of activation of the renin–angiotensin system. EP1 receptor knockout mice not only exhibit reduced blood pressure on normal chow, but also impaired pressor response to angiotensin II. These studies identified EP1 mRNA expression in small resistance vessels of mice including the afferent arterioles of the glomerulus, and are consistent with more recent studies suggesting Ang II-stimulated vasoconstriction may in part be mediated by activation of vascular EP1 receptors. EP1 receptors have also been identified in glomerular mesangial cells, where they may contribute to mesangial contraction. Inhibition of the EP1 receptor slows the progression of mesangial expansion in experimental models of diabetic nephropathy. EP1 receptor knockout mice are resistant to the pressor effects of angiotensin II, and EP1 receptor antagonists can also block the Ang II pressor activity. It is instructive to consider the role of PGE 2 as a vasoconstrictor through its actions on the EP1 receptor, as opposed to its classically characterized role as a vasodilator/vasodepressor. This underscores the capacity of PGE 2 to serve as a physiological buffer of blood pressure, either in support or reduction of blood pressure (see below).

EP 2 Receptors

In contrast to the smooth muscle constrictor activity of the EP1 receptor, the EP2 receptor was originally defined by its relaxant activity in smooth muscle. The human EP 2 receptor cDNA encodes a 358 amino acid polypeptide, which signals through increased cAMP and is selectively activated by butaprost. The EP 2 receptor may be distinguished from the EP 4 receptor, the other major cAMP stimulating and vasorelaxant EP receptor, by its selective activation by butaprost and relative insensitivity to the EP 4 agonist PGE 1 -OH. Literature prior to 1995 may be confusing regarding the EP 2 receptor, because before the human EP 2 receptor was cloned, the previously cloned EP 4 receptor was classified as the EP 2 receptor.

The physiological processes mediated by the EP2 receptor include important roles in reproduction and blood pressure regulation. The precise tissue distribution of the EP 2 receptor has only been characterized by Northern blot analysis of mRNA distribution. This reveals a major mRNA species of ~3.1 kb that is most abundant in the uterus, lung, and spleen, exhibiting only low levels of expression in the kidney. EP2 knockout mice exhibit a fertility defect and the development of hypertension on a high NaCl diet (these latter effects are significantly influenced by the genetic background of the mouse strain). In the kidney, despite incomplete histological characterization, a preponderance of functional and mRNA expression evidence suggests the EP2 receptor is expressed in stromal cells of the kidney, including renal medullary interstitial cells, vascular pericytes along the vasa recta, and glomerular arterioles where it contributes to afferent arteriolar dilation ( Figure 17.4 ). Evidence suggests that deletion of the EP2 receptor in renal medullary interstitial cells, combined with the absence of its systemic vasodilator activity, contributes to salt-sensitive hypertension in the EP2 knockout mouse.

Figure 17.4

Schematic of prostanoid receptor action at the afferent arteriole including EP1, EP2, EP3, EP4, and IP receptors.

(From ref. , with permission from Am J. Physiol.)

EP 3 Receptor

In smooth muscle the EP 3 receptor generally acts as a constrictor. This receptor is unique, in that at least seven alternatively spliced variants defined by unique COOH-terminal cytoplasmic tails exist in humans alone, and over 22 unique variants have been observed in rats, rabbits, mice, cows, and humans. These splice variants encode proteins of a predicted molecular mass between 40 and 45 kDa. All the EP 3 splice variants bind PGE 2 and the EP 3 specific prostanoid analogs with similar affinity, and inhibit cAMP generation via a pertussis toxin-sensitive G i -coupled mechanism; however, additional signaling mechanisms may be differentially activated by the different COOH-terminal tails.

Mice with targeted deletion of the EP 3 receptor exhibit an impaired febrile response to lipopolysaccaride and PGE 2 , suggesting that the EP 3 receptor antagonists could be effective antipyretic agents. In the kidney the EP 3 receptor is highly expressed in the cortical and outer medullary collecting duct, where it antagonizes vasopressin-stimulated water absorption via pertussis toxin-sensitive inhibition of cAMP generation. Despite relatively high levels of EP 3 receptor in the kidney collecting duct, mice with targeted disruption of this receptor only display a subtle alteration with altered urinary concentrating ability in mice treated with NSAIDs. These findings raise the possibility that prostaglandin receptors other than the EP 3 receptor exert overlapping effects that also (such as the EP1 and FP receptor) modulate the urinary concentration and dilution by this segment of the nephron.

EP 4 Receptor

The EP 4 receptor can be distinguished from the EP 1 and EP 3 receptors by its insensitivity to sulprostone, and from EP 2 receptors by its insensitivity to butaprost and relatively selective activation by PGE 1 -OH. The human EP 4 receptor cDNA encodes a 488 amino acid polypeptide with a predicted molecular mass of ~53 kDa. Like the EP 2 receptor, EP 4 signals through increased cAMP, but may also engage other signaling mechanisms including PI3K activation. EP 4 receptor mRNA is relatively highly expressed compared with the EP 2 receptor and widely distributed, with a major species of ~3.8 kb detected by Northern analysis in thymus, ileum, lung, spleen, adrenal gland, and kidney. In contrast to other EP receptor knockouts, EP4 receptor knockout mice exhibit a profound perinatal lethal phenotype due to impaired closure of the ductus arteriosus, consistent with its robust expression in this vessel.

In the kidney, EP4 receptor mRNA is predominantly expressed in the glomerulus where it modulates glomerular hemodynamics through opposing direct vasodilator activity, and an indirect vasoconstrictor activity via stimulation of renin release ( Figure 17.4 ). The ability of PGE 2 to increase renin release is well-established and of clinical relevance, since NSAID blockade of prostaglandin synthesis can be associated with hyporeninemic hypoaldosteronism, and COX2 inhibitors can block the hyper-reninemia associated with volume depletion or Bartter’s syndrome. Accumulating evidence supports a role for COX2-mediated PGE 2 production, and subsequent activation of juxtaglomerular EP4 receptor in mediating renin release. As mPGES-specific inhibitors and EP4 receptor antagonists become increasingly available it will be important to determine the relative contribution of PGE2-dependent renin release versus prostacyclin-dependent effects (see below).

In volume depletion, congestive heart failure, and shock, intrarenal PGE 2 production helps maintain glomerular perfusion via afferent arteriolar vasodilator EP2 receptors ( Figure 17.4 ), while simultaneously maintaining systemic blood pressure by stimulating renin release through EP4 receptors. Genetic deletion of the EP4 receptor or EP4 inhibitors impairs renin release in mice following furosemide-induced volume depletion. Inhibition of PGE 2 synthesis using NSAIDs or COX2 inhibition in these settings can actually drop blood pressure by inhibiting renin release, and lead to acute renal failure due to decreased glomerular perfusion.

The EP4 receptor is also abundant in glomerular podocytes. In podocytes EP4 receptor activation may impair their ability to withstand mechanical stress, since podocyte selective overexpression of EP4 receptors accelerates renal injury in a mouse renal ablation model of kidney disease.

Other roles for the EP4 receptor in controlling blood pressure have been suggested, including the ability to stimulate aldosterone release from zona glomerulosa cells. It remains to be determined whether the adrenal EP4 receptor plays any role in hyperkalemia and hyporeninemic hypoaldosteronism associated with NSAID blockade of prostaglandin synthesis or whether this is primarily due to hyporeninemia. Important vasodilator effects of EP 4 receptor activation in venous and arterial beds have been described. Roles for EP4 receptors in immune cell activation and osteoblast function have also been reported.

Prostaglandin F Synthesis

PGF may derive either directly from PGH 2 via a PGF synthase or via a NADPH-dependent 9 ketoreductase, which converts PGE 2 into PGF . This enzymatic activity is typically cytosolic, and may be detected in homogenates from renal cortex, medulla or papilla. Another more obscure pathway for PGF formation is by the action of a PGD 2 ketoreductase, yielding a stereoisomer of PGF , 9α,11ß-PGF 2 (11epi-PGF ). This reaction, and conversion of PGD 2 into the biologically active metabolite (9α,11β-PGF ) has been documented in vivo . This PGF isomer can also ligate and activate the FP receptor. The physiologically relevant enzymes responsible for PGF formation in the kidney remain incompletely characterized.

Prostaglandin 9-Ketoreductase (PG9KR) and PGF Synthesis

Prostaglandin F synthase activity may be mediated via several distinct, and incompletely defined, enzymes. One major synthetic pathway appears to occur via a member of the aldo-ketoreductase 1C family. Renal PGE 2 9-ketoreductase also exhibits 20α-hydroxyl-steroid reductase activity that may be involved in steroid metabolism. PG9KR activity appears to be particularly robust in suspensions from the thick ascending limb of Henle (TALH).

Interestingly, some studies suggest activity of a 9-ketoreductase may be modulated by salt intake and the angiotensin AT2 receptor. This activity may play a role in the development of salt-sensitive hypertension. AT2 receptor knockout mice exhibit salt-sensitive hypertension associated with increased PGE 2 production and reduced production of PGF , consistent with decreased 9-ketoreductase activity. Other studies suggest increased dietary potassium intake may also enhance the activity of conversion from PGE 2 to PGF . The intrarenal sites of expression of this enzymatic activity remain to be characterized.

F-Prostanoid Receptors

Once formed, PGF is available to interact with the intrarenal FP receptors. The human FP receptor mRNA is predicted to encode 359 amino acid residues with a molecular mass of ~40 kDa. In fibroblasts and smooth muscle the FP receptor signals through increased cellular calcium, and its activation is associated with muscle contraction. The FP receptor is highly expressed in the ovarian corpus luteum, and mice lacking the FP receptor exhibit a major reproductive defect due to failure of partuition because of impaired reduction of progesterone at term. FP receptor antagonists have been developed, and their use proposed as a means of delaying pre-term delivery. The FP receptor is highly expressed in the ocular ciliary body and FP selective agonists including travaprost, latanoprost, and bimatoprost are in use for clinical treatment of glaucoma d. In the kidney, the FP receptor is highly expressed in the distal convoluted tubule, connecting tubule, and cortical collecting duct, where it inhibits vasopressin-stimulated renal water transport consistent with recent studies that the FP receptor knockout mice exhibit mild polyuria and polydipsia. Interestingly, in the rabbit cortical collecting duct epithelium the FP receptor appears to signal through a pertussis toxin-sensitive G i -coupled mechanism, rather than the classical Ca 2+ -coupled signaling mechanism observed in smooth muscle cells. Vascular expression of FP receptor in pre-glomerular arterioles and other resistance vessels has also been demonstrated, and studies in FP receptor knockout mice show they are relatively hypotensive. These studies also provide evidence that renal JGA FP receptor activation directly stimulates renin release.

Prostaglandin D 2 is derived from PGH 2 via the action of specific enzymes designated PGD synthases. Two major enzymes are capable of transforming PGH 2 to PGD 2 – a lipocalin type PGD synthase and a hematopoietic type PGDS. RT-PCR showed that L-PGDS is strongly expressed in kidney cortex and outer medulla, including in nearly all segments of the nephron, while H-PGDS mRNA is only detected in microdissected outer medullary collecting duct.

Lipocalin PGD synthase (L-PGDS) is a multifunctional molecule, and on addition to prostaglandin H2 it binds a variety of small lipophilic molecules including bilirubin and biliverdin. Mice lacking the lipocalin D synthase gene exhibit pain sensation. LPGDS-mediated PGD2 synthesis also appears to play an important role in the sleep/wake cycle, but its role in renal PGD2 synthesis has not been studied. Urinary levels of L-PGDS, also known as beta-trace protein, have been increasingly studied as a biomarker of acute and chronic renal injury. LPDGS knockout mice appear to be more susceptible to diabetic nephropathy.

PGD 2 is the major prostanoid released from mast cells following challenge with IgE, and this synthesis appears to be mediated by the hematopoietic form of PGDS. The precise role of hematopoietic PGDS in the kidney remains uncertain, as does the significance of its reported localization in the outer medullary collecting duct.

D-Prostanoid Receptors

Once synthesized, PGD 2 is available to interact with either the DP1 or DP2 (originally identified as CRTH2) receptors or undergo further metabolism to a PGF 2 -like compound that can interact with the FP receptor (see above). The human DP1 receptor is a cAMP-coupled GPCR with a predicted molecular mass similar to other prostanoid receptors (~40 kDa). It exhibits a relatively selective tissue distribution, with particularly high expression in retina and small intestine, where it appears to be highly expressed in mucus secreting goblet cells. The DP2 receptor is a GPCR that is also activated by PGD2, but it is unrelated in sequence to the classic prostanoid receptor family, being more closely related to members of the N -formyl peptide receptor (FPR) subfamily. DP2 is selectively expressed in Th2 cells, cytotoxic T-cells, eosinophils, and basophils. DP and DP2 receptors are intimately involved in the immune allergic response. Neither DP1 receptors nor DP2 receptors appear to be highly expressed in the kidney, and while infusion of a DP1 selective agonist lowers blood pressure these effects appear to be primarily due to peripheral vasodilation and not by directly affecting renal blood flow.

Prostacyclin (PGI 2 )

The biological effects of prostacyclin are numerous and include nocioception, anti-thrombosis, and vasodilator actions, which have been targeted therapeutically to treat pulmonary hypertension. Prostacyclin (PGI 2 ) is derived from the enzymatic conversion of PGH 2 via prostacyclin synthase (PGIS) to PGI 2 . The PGIS cDNA is comprised of a 1500 bp open reading frame that encodes a 500 amino acid protein of approximately 56 kDa. Northern blot analysis shows prostacyclin synthase mRNA is widely expressed in human tissues and is particularly abundant in ovary, heart, skeletal muscle, lung, and prostate. PGI synthase expression exhibits segmental expression in the kidney, especially in kidney inner medulla tubules and interstitial cells.

PGI 2 synthase-null mice exhibit a profound renal phenotype with nephrosclerosis and areas of renal infarction. PGI 2 levels in the plasma, kidneys, and lungs were reduced, documenting the role of this enzyme as an in vivo source of PGI 2 . Blood pressure and blood urea nitrogen and creatinine in the PGIS knockout mice were significantly increased, and renal pathological findings included surface irregularity, fibrosis, cysts, arterial sclerosis, and hypertrophy of vessel walls. Thickening of the thoracic aortic media and adventitia were observed in aged PGIS-null mice. Interestingly, this is a phenotype different from that reported for the IP receptor knockout mouse, which failed to exhibit abnormal kidney morphology. These differences suggests the presence of additional IP receptor independent PGI 2 activated signaling pathways – possibly through nuclear receptors such as PPARdelta. Regardless, these findings demonstrate the importance of PGI 2 in the maintenance of blood vessels and to the kidney.

IP Receptor

The IP receptor mRNA is highly expressed in the afferent arteriole, where it may combine with the effects of EP2 and EP4 receptors to dilate renal arterioles and stimulate renin release. IP receptor deficient mice exhibit reduced renin and are resistant to the development of hypertension following unilateral renal artery stenosis, consistent with an impaired IP receptor-mediated renin release. COX2-derived prostacyclin from the endothelium also appears to serve an atheroprotective role in mice, and its loss could contribute to the cardiovascular risks associated with the use of COX2 inhibitors. Conversely, thromboxane receptors may counteract the effects of these protective effects of prostacyclin and accelerate atherosclerotic lesions, as well as increasing vascular resistance.

Thromboxane A2

Thromboxane A 2 (TxA 2 ) is produced from PGH 2 by thromboxane synthase (TxAS), a microsomal protein of 533 amino acids with a predicted molecular weight of ~60 kDa. The human gene is located on chromosome 7q, and the enzyme exhibits homology to the cytochrome P450s and is now classified as CYP5A1. TxAS mRNA is highly expressed in hematopoietic cells, including platelets, macrophages, and leukocytes, as well as thymus, kidney, lung, spleen, prostate, and placenta. Immunolocalization of TxA synthase demonstrates high expression in the dendritic cells of the interstitium, with lower expression in glomerular podocytes of human kidney. In the kidney, thromboxane synthase is mainly detected in the glomeruli. TxA 2 synthase expression is regulated by dietary salt intake. Furthermore, experimental use of ridogrel, a specific thromboxane synthase inhibitor, reduced blood pressure in spontaneously hypertensive rats. The clinical use of TxA 2 synthase inhibitors is complicated by the fact that its endoperoxide precursors (PGG 2 /PGH 2 ) are also capable of activating its downstream target, the TP receptor, so thromboxane receptor antagonists would be expected to more definitively interfere with this pathway.

TP Receptor

The thromboxane receptor (TP) was the first member of the prostanoid receptor family cloned. This GPCR has a predicted molecular mass ~37.5 kDa, and is highly expressed in platelets and vascular tissue where its activation increases intracellular calcium. In the kidney TP receptor mRNA is predominantly expressed in the glomerulus and vascular tissue, where it contributes to vasoconstrictor activity following Ang II infusion and following renal injury.

Prostaglandin Transport

One of the major areas of uncertainty in eicosanoid research is precisely how prostanoids, synthesized inside the cell, transit the cell membrane to become available to interact with cell surface receptors. Recent studies have identified several transmembrane proteins capable of facilitated transport of prostaglandins across cell membranes. Schuster’s group identified a lactate/PGE 2 exchanger they designated prostaglandin transporter or PGT. The importance of PGT in mediating the in vivo effects of PGE 2 has been substantially bolstered by studies showing genetic disruption of the PGT gene is associated with perinatal death due to persistence of a patent ductus arteriosus recapitulating the phenotype of the EP4 receptor knockout. Although this prostaglandin transporter appears poised primarily to provide a PGE2 re-uptake mechanism, it is notable that the transporter is expressed in renal cells that are major sites of prostaglandin synthesis, rather than those renal cells involved in PGE 2 inactivation. These findings are consistent with the possibility that PGT plays an important role in directing vectorial PGE 2 release. Nevertheless, it seems unlikely that this protein comprises the pathway mediating PGE 2 release. More recent evidence supports a role for the multi-drug resistance protein 4 (MRP4) as a potential PGE 2 efflux mechanism. MRP4 knockout mice exhibit low levels of circulating PGE 2 and reduced inflammatory pain, consistent with a role in PGE2 extrusion.

Prostaglandins and the Pathogenesis of Kidney Disease

Renal Inflammation

Increased glomerular COX1 or COX2 expression has been reported in patients with nephritis, and in animal models of nephritis. Glomerular expression of COX2 is upregulated in patients with active lupus nephritis and in lupus nephritis animal models. COX2 inhibition has shown beneficial effects on passive Heymann nephritis (PHN), a model of membranous nephropathy. Cell culture studies show that thromboxane A2 contributes to complement-induced cytotoxicity of glomerular epithelial cells. In contrast, in anti-Thy1.1 glomerulonephritis model, an animal model of mesangioproliferative glomerulonephritis (MPGN) that is characterized by endothelial injury, COX2 inhibition is associated with increased mesangiolysis, albuminuria, and delayed recovery from glomerular injury. Further studies suggest that healing of injured glomerular capillary endothelium in this model may depend on COX2-derived prostanoids, and COX2 inhibition may lead to impaired capillary endothelium healing. The role of COX-derived prostanoids in autoimmune and inflammatory disease has been well-documented. COX2 expression and prostanoid biosynthesis can be induced in macrophages and dendritic cells by inflammatory agents, such as LPS, IL-1ß, and interferon. PGDS expression or activity has been described in dendritic cells, macrophage, eosinophil, neutrophil, and mast cells. Prostanoids, particularly PGE2 and PGI2, have been shown to enhance inflammatory reactions. Conversely prostanoids also exert anti-inflammatory effects. The pro- or anti-inflammatory effect of prostanoids is dependent on specific prostanoid, receptor subtype, cell population, and context of activation. Additional studies are required to define the precise roles of prostanoids in different forms of glomerulonephritis.

Renal COX-Derived Prostanoids and Diabetic Nephropathy

Diabetic nephropathy is characterized by microalbuminuria, glomerular hypertrophy, mesangial expansion with glomerular basement membrane thickening, arteriolar hyalinosis, and global glomerular sclerosis, which ultimately lead to the progression to proteinuria and renal failure. Supra-normal GFR (hyperfiltration) typifies the early stages of diabetic nephropathy. Studies in diabetic humans and streptozotocin (STZ)-induced type I diabetic rats show increased renal PGE2, PGI2, and TxB2 levels. COX2 expression is increased in the thick ascending limb and macula densa in diabetic humans and rodents. Selective COX2 inhibition reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats, consistent with COX2-derived prostanoids increasing renal blood flow in the diabetic kidney. The identity of the specific COX2-derived prostanoids and their cognate receptors involved in pathogenesis of diabetic hyperfiltration has not been completely characterized. EP1 receptor antagonist treatment ameliorates renal and glomerular hypertrophy, and decreases mesangial expansion. A thromboxane receptor (TP) antagonist has also been reported to attenuate proteinuria and ameliorate histological changes of diabetic nephropathy in diabetic apolipoprotein E-deficient mice. It has not been determined whether similar beneficial effects might be observed in human diabetic nephropathy.

Prostaglandins and Progression of Kidney Disease

COX-derived prostanoids may also modify renal function and glomerular damage in non-diabetic chronic renal disease. After subtotal renal ablation, renal cortical COX2 expression is increased, predominantly in the macula densa and surrounding cTAL. Selective COX2 inhibition decreases proteinuria and inhibits the development of glomerular sclerosis. These studies are consistent with a role of COX2-derived prostanoids in the pathogenesis of structural and functional deterioration of kidney in chronic kidney disease.

Lipoxygenase Derived Eicosanoids: 5-, 12-, and 15-HETEs and Leukotrienes

Arachidonic acid may be metabolized to form leukotrienes and hydroxyeicosatetraenoic acids (HETEs) by a family of enzymes designated lipoxygenases ( Figure 17.5 ). Leukotriene arachidonic acid metabolites play a major role in inflammatory disease, especially asthma and other inflammatory pulmonary diseases where cysteinyl leukotriene receptor antagonists have found a place as a standard of care. In contrast to the prostaglandins, it has been difficult to demonstrate a major role for leukotrienes in the normal kidney.

Figure 17.5

Leukotriene synthetic pathway.

Lipoxygenases (LOX) are comprised of non-heme iron containing enzymes that insert molecular oxygen into polyunsaturated fatty acids such as arachidonic acid and linoleic acid. Six functional human lipoxygenases have been cloned: 5-lipoxygenase (gene name: ALOX5); platelet-type 12-lipoxygenase (gene name: ALOX12); 12/15-lipoxygenase (leukocyte-type 12-LO for mice, 15-LO type 1 for human, gene name: ALOX15); epidermal-type 12-lipoxgenase (gene name: ALOXE3); 12(R)-lipoxygenase (gene name: ALOX12B); and 15-lipoxygenase type 2 (gene name: ALOX15B, 8-lipoxygenase in mice).

5-Lipoxygenase is the key enzyme in leukotriene biosynthesis. In the presence of 5-LO-activating protein (FLAP) 5-lipoxygenase catalyzes the generation of leukotriene A4 (LTA4). LTA4, in turn, is converted by LTA4 hydrolase to LTB4, capable of activating LTB4 receptors. LTB4 is a potent chemotactic substance, and increases polymorphonuclear leukocytes (PMN) aggregation and adhesion to the endothelium. Alternatively, LTA4 can be converted to cysteinyl (cys) leukotrienes (LTC4, LTD4, and LTE4) through leukotriene C4 synthase. LTC4 and LTD4 contract vascular smooth muscle cells and increase vascular permeability. These leukotrienes are usually released locally by leukocytes. Mice with 5-LO gene disruption exhibit a reduced inflammatory reaction, supporting the pro-inflammatory action of 5-LO-derived metabolites. Recently, increased expression of leukotriene C4 synthase and formation of cysteinyl-leukotrienes have been reported in human abdominal aortic aneurysm.

As might be predicted from its expression in inflammatory cells, 5-LO-derived products appear to play an important role in glomerular immune injury. 5-LO mRNA and 5-LOX-activating protein (FLAP) mRNA are detected in the glomeruli and vasa recta. Both leukotriene receptor B4 and the cysteinyl leukotriene receptor type 1 are selectively expressed in the glomerulus, suggesting 5-LO products are involved in glomerular function. Glomerular synthesis of LTB4 and LTC4/LTD4 is markedly enhanced in both human disease and experimental glomerular immune injury. LTD4 may contribute to the reduction of GFR in the acute phase of injury by virtue of its potent vasoconstrictor action and contraction of mesangial cells. LTD4 may also increase intraglomerular pressure, contributing to proteinuria. LTB4, a potent promoter of PMN attraction, participates in glomerular damage by amplifying PMN-dependent mechanisms of injury.

The biological functions of the other members of the lipoxygenase family are more obscure. The 12-LO, catalyzes the formation of oxidized lipids 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE]. Human 15-LO type 1 shares high homology with rodent leukocyte-type 12-LO; both can mediate the formation of 12(S)-HETE and 15(S)-HETE from arachidonic acid, and are thus classified as 12/15-LO. Some evidence suggests that 12(S)-HETE and 15(S)-HETE play important roles in systemic homeostasis and renal–cardiovascular pathology ; however, specific receptors for these products have not yet been identified. A recent study implicates ALOX15 as playing a role in bone mineralization. 12/15-Lipoxygenase products also appear to be involved in the pathogenesis of atherosclerosis.

12/15-Lipoxygenase-derived products may contribute to the pathogenesis of diabetic complications, including diabetic nephropathy. 12/15-LO is detected in renal microvessels, glomeruli, and mesangial cells. 12/15-LO levels are increased in the glomeruli of experimental diabetic animals. The 12/15 LO pathway has been shown to be a critical mediator of TGFβ and angiotensin II (ANG II)-induced mesangial cell hypertrophy and extracellular matrix accumulation. These studies also suggest that ANG II-induced mesangial cell hypertrophy and extracellular matrix synthesis in cultured rat mesangial cells can be blocked by an LO inhibitor or targeted 12/15 LO gene deletion.

Cytochrome P450 Monooxygenase-Derived Eicosanoids: 20-HETE and EETs

Free arachidonic acid can also be metabolized by the cytochrome P450 monooxygenases (CYP450) to produce hydroxy- and epoxy-arachidonic acid derivatives. The major CYP450-catalyzed reactions in most tissues are mediated by epoxygenase and ω-hydroxylase activities of the CYP450 family, which are responsible for biosynthesis of epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), respectively ( Figure 17.6 ). These metabolites have been shown to possess biological activity, but the mechanisms mediating these biological effects remain obscure since specific receptors have not been identified.

Figure 17.6

Products of cytochrome P450-mediated metabolism of arachidonic acid.

Members of the P450 CYP2C , and 2J subfamilies have been identified as functionally relevant epoxygenases, while members of 4A and 4F are ω-hydroxylases, respectively. 20-HETE is a potent vasoconstrictor. EETs are produced in the vascular endothelium, and are potent vasodilators. EETs are also produced in tubules, including the proximal tubule and collecting ducts in the rodent kidney. EETs have been shown to inhibit ENaC activity, which may contribute to their natriuretic effect. EETs have also been shown to mediate the natriuretic effect of angiotensin II. Studies of knockout mice have supported a role for CYP450 metabolism in the regulation of blood pressure, but the mechanisms of these effects remain incompletely understood. Genetic disruption of CYP2J8 was associated with hypertension in females, but it is uncertain whether this effect is related to its arachidonate epoxygenase activity in mice or an effect on estrogen metabolism. Genetic disruption of cyp4a10 and 4a14 are also associated with hypertension, adding to uncertainty regarding the distinct roles of epoxygenase and ω-hydroxylase activity of arachidonic acid in regulating vascular tone and blood pressure.

Role of Renal CYP450-Derived Arachidonate Metabolites in Renal Damage

Increased EET formation has been reported in the kidney of rats with liver cirrhosis. While it is well-documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, this result suggests increased EET synthesis may be a homeostatic response to help preserve renal perfusion. Reduced CYP arachidonate hydroxyglase activity and 20-HETE levels have been reported in the kidney following ischemia and reperfusion. Reduced CYP4A protein expression and enzyme activity in ischemia/reperfusion was suggested as an adaptive mechanism to preserve renal vasculature from excessive vasoconstriction. Other studies suggest that the CYP hydroxylase-derived product 20-HETE plays an important role in the maintenance of the glomerular protein permeability barrier. An in vitro glomerular albumin permeability study using isolated rat glomeruli shows that puromycin aminonucleoside (PAN) significantly increases glomerular albumin permeability. 20-HETE treatment blocks PAN-induced increase in albumin permeability.


Eicosanoids exert diverse and sometimes self-opposing functions. The specific effect of each eicosanoid depends on sequential enzymatic machinery in a specific cell, yielding a specific eicosanoid, exerting its distinct function. The biosynthesis of each eicosanoid is regulated at multiple levels from phospholipase A2 that catalyzes the release of arachidonic acid to specific enzymes that catalyze the formation of bioactive eicosanoids. Arachidonate-derived eicosanoids including prostanoids, leukotrienes, 12/15-HETEs, EETs, and HETEs, and sphingomyelin-derived ceramide play important roles in maintaining normal renal function. They are also involved in the pathophysiology of diabetic nephropathy, and inflammatory or toxic glomerular injury. Those signaling pathways should provide a fruitful area to identify targets for intervention in the pharmacologic treatment of renal disease.


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Jun 6, 2019 | Posted by in NEPHROLOGY | Comments Off on Eicosanoids and Renal Function
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