View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector http://www.kidney-international.org review & 2007 International Society of Nephrology

Physiologic and pathophysiologic roles of lipid mediators in the kidney C-M Hao1 and MD Breyer1

1Division of Nephrology, Department of Medicine, Vanderbilt University, and Veterans Administration Medical Center, Nashville, Tennessee, USA

Small lipids such as eicosanoids exert diverse and complex An extensive body of evidence demonstrates that small lipids functions. In addition to their role in regulating normal participate as mediators in a variety of trans-membrane kidney function, these lipids also play important roles in the signaling cascades, mediating multiple cellular processes such pathogenesis of kidney diseases. Cyclooxygenase as cell differentiation, replication, and apoptosis.1–4 These (COX)-derived play important role in maintaining lipids include eicosanoids, fatty acids, glycerophospholipids, renal function, body fluid homeostasis, and blood pressure. and ceramides.1–4 In addition to their roles in regulating Renal cortical COX2-derived prostanoids, particularly (PGI2) physiologic function, these lipid mediators have also been and PGE2 play critical roles in maintaining blood pressure demonstrated to play important roles in the pathophysiology and renal function in volume contracted states. Renal medullary of inflammation, asthma, cancer, diabetes, and hyperten- COX2-derived prostanoids appear to have antihypertensive sion,1–5 pointing to potential therapeutic targets at these lipid effect in individuals challenged with a high salt diet. mediators or the responsible for their biosynthesis or 5-Lipoxygenase (LO)-derived leukotrienes are involved the mediating their actions. The present review will in inflammatory glomerular injury. LO product focus on the current understanding of the roles of 12-hydroxyeicosatetraenoic acid (12-HETE) is associated with -derived lipid mediators in mediating pathogenesis of hypertension, and may mediate angiotensin normal physiologic function and pathologic events of the II and TGFb induced mesengial cell abnormality in diabetic kidney. nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of EICOSANOIDS hypertension. P450 epoxygenase derived Eicosanoids are 20 carbon fatty acid derivatives (eicosa, epoxyeicosatrienoic acids (EETs) have vasodilator and Greek for 20), produced from arachidonic acid through three natriuretic effect. Blockade of EET formation is associated major enzymatic pathways: cyclooxygenase (COX), lipoxy- with salt-sensitive hypertension. Ceramide has also been genase (LO), and cytochrome P450 monooxygenase demonstrated to be an important signaling molecule, which (CYP450).2,3,5–7 Eicosanoids include prostanoids derived is involved in pathogenesis of acute kidney injury caused by from COX pathway, leukotrienes from LO pathway and ischemia/reperfusion, and toxic insults. Those pathways hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatri- should provide fruitful targets for intervention in the enoic acids (EETs) from P450 monooxygenase pathway.2,3,5–7 pharmacologic treatment of renal disease. Kidney International (2007) 71, 1105–1115; doi:10.1038/sj.ki.5002192; ARACHIDONIC ACID AND PHOSPHOLIPASE A2 published online 14 March 2007 Arachidonic acid, a precursor of eicosanoids, exists primarily KEYWORDS: eicosanoid; ; ceramide; hypertension; diabetic in esterified form as a glycerophospholipid in the cell nephropathy; nephritis membrane. Cellular levels of free arachidonic acid available for eicosanoid production is primarily controlled by phospholipase A2 (PLA2).8 Thus far more than 20 PLA2s have been identified, which have been classified into four groups: secretory PLA2 (sPLA2), cytosolic PLA2 (cPLA2), calcium independent PLA2 (iPLA2), and PAF acetylhydro- lases (PAF-AH).8,9 Five members of cPLA2 family have been identified: cPLA2a, b, d, e, z, and g.10 Among them, cPLA2a Correspondence: C-M Hao, S3223 MCN, Division of Nephrology, (IVA PLA2) is best characterized and is suggested to be a key Department of Medicine, Vanderbilt University and Veterans Administration 8,9 Medical Center, Nashville, Tennessee 37232, USA. player for arachidonic acid release. cPLA2 can be E-mail: [email protected] phosphorylated by several kinases including mito- Received 23 January 2007; accepted 30 January 2007; published online gen-activated protein kinase, protein kinase C (PKC), and 2 þ 11–13 14 March 2007 Ca -calmodulin-dependent kinase. Several vasoactive

Kidney International (2007) 71, 1105–1115 1105 review C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators

substances, such as endothelin, angiotensin II (ANG II), and COOH vasopressin, have been reported to activate cPLA2.14–20 Arachidonate These properties of cPLA2 are consistent with its critical role in regulating arachidonic acid release and eicosanoid Cox biosynthesis.8,9 O COOH In the kidney, PLA2 activity can be induced by a variety of PGH2 O stimuli, including oxidative stress, complement C5b-9, 21–24 OH hypoxia, and mechanical stretch. It has been documented PGES PGFS TxS PGIS PGDS that cPLA2 can potentiate H2O2 cytotoxicity in kidney epithelial cells and glomerular mesangial cells.25,26 cPLA2 and PGES2 PGl2 PGD PGF  TxA2 its products have been reported to participate in several 2 2 pathogenic process, including diabetic nephropathy, anti- Thy1 glomerulonephritis, and ischemic kidney injury.8,10 Recently, considerable evidence suggests that secretary PLA2s, EP1 P1 DP FP TP particularly secretory PLA2 IIa, secretory PLA2 V, and EP2 secretory PLA2 X, are involved in atherosclerotic lesions.27–29 EP3 Their roles in the kidney remain to be defined. EP4 Figure 1 | Cyclooxygenase pathway of arachidonic acid COX-DERIVED PROSTANOIDS metabolism. Prostanoids are formed by conversion of free arachidonic acid to a common intermediate, PGH2 by COX via two enzymatic processes (Figure 1). COX first converts arachi- role of COX2 in maintaining cardiovascular homeostasis.46–48 donic acid to PGG2 via its bis-oxygenase activity, and the In the kidney, COX1 is highly expressed in the collecting unstable PGG2 is then converted to PGH2 by the peroxidase duct, and low level of COX1 can also be detected in activity of COX.30 PGH2 is subsequently metabolized to interstitial cells.49–51 In contrast, COX2 is predominately more stable biologically active prostanoids including PGE2, expressed in renal medullary interstitial cells and in cortical prostacyclin (PGI2), PGF2a, PGD2, and thromboxane A2 by thick ascending limb and cells associated with macula densa distinct synthases. Each prostanoid acts on specific and under normal conditions.38,49,52 distinct cell surface G-protein coupled receptor(s)31,32 or on PGH2, the product of COX-mediated arachidonate nuclear receptors such as peroxisome proliferator activated metabolism, is further metabolized by prostanoid synthase. receptor (PPAR)d and PPARg33–36(Figure 1). Prostanoid synthases include PGE2 synthase (PGES), Prostanoids are rapidly metabolically degraded, limiting prostacyclin synthase (PGIS), PGD synthase (PGDS), their effect to the immediate vicinity of their synthetic site, PGF synthase (PGFS), and thromboxane synthase, respon- accounting for their autocrine or paracrine function. The sible for PGE2, PGI2, PGD2, PGF2a, and thromboxane biologic effects of COX-derived prostanoids are diverse and A2 biosynthesis, respectively.41,53 At least three PGE complex, depending on which prostanoid is produced and synthases have been identified: microsomal PGE synthase 1 which receptor is available.31,32 Thus the effects of prosta- (mPGES1), microsomal PGE synthase 2 (mPGES), and noids on kidney function will rely on distinct enzymatic cytosolic PGE synthase (cPGES1).54–56 mPGES1 displays machinery that couples phospholipase and COX to specific a high catalytic activity relative to other PGESs.54,57 The prostanoid synthase in specific cells, yielding a specific expression of mPGES1 is induced by cytokines and prostanoid, which acts, through autocrine or paracrine, on a inflammatory stimuli.54 In contrast, the expression of cPGES specific G-protein coupled receptor, exerting its distinct and mPGES2 is not inducible.56,58 PGD2 is synthesized effect.31 from PGH2 catalyzed by PGD synthase (PGDS).59 Two Two isoforms of COX have been identified, designated distinct types of PGDS have been identified: the lipocalin- COX1 and COX2.37–40 COX1 appears to serve a constitutive type PGDS (L-PGDS) and the hematopoietic PGDS (H- house-keeping role, responsible for maintaining basic PGDS).59,60 PGF2a can be synthesized from PGH2 by 9,11 physiological function such as cytoprotection of the gastric endoperoxide reductase.61 PGF2a can also be synthesized mucosa, and control of platelet aggregation.6,30,41 Conversely, from PGE2 by PGE 9-ketoreductase.62,63 The distribution COX2 is induced by inflammatory mediators and mitogens, of prostanoid synthases within the kidney is less well and is thought to play a key role in pathophysiologic characterized. In the kidney, mPGES1 is expressed in processes including angiogenesis, inflammation, and tumor- collecting duct and medullary interstitial cells.64,65 Although igenesis.6,7,30,41 However, recent studies indicate that COX2 mPGES1 has been reported to be functionally coupled also serves ‘house-keeping’ functions. targeting experi- to COX2,58 in renal collecting duct mPGES1 appears to be ments demonstrated a critical role of COX2 in kidney mainly coupled to COX1.64 Low levels of mPGES2 and development, in ovulation and parturition.42–45 Clinical cPGES are also detected in the kidney.66,67 Thromboxane studies as well as animal studies also demonstrated important synthase is mainly detected in glomeruli.65 PGIS appears

1106 Kidney International (2007) 71, 1105–1115 C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators review

to be mainly localized to vasculature in the kidney.65 Effect of renal prostanoids on renal hemodynamics and its RT-PCR showed that L-PGDS is strongly expressed in kidney role in acute renal failure cortex and outer medulla. Whereas H-PGDS mRNA is only It has long been recognized that COX-derived prostanoids detected in microdissected outer medullary collecting duct.65 play a critical role in modulating renal blood flow (RBF) and 74–76 PGE2 is the most abundant prostanoid in the kidney, glomerular filtration rate (GFR). Under normal condi- followed by PGI2, PGF2a, and thromboxane A2.68 Under tions, prostanoids seem to exert little influence on RBF and 74 basal conditions, both COX1 and COX2 pathways are GFR. However, under certain pathophysiological condi- responsible for the biosynthesis of these prostanoids.68 In tions, particularly in the setting of volume contracted state contrast, the COX2 pathway contributes to angiotensin II- such as congestive heart failure, cirrhosis with ascites, and induced PGE2 and PGI2 generation in the kidney.68 The nephrotic syndrome, maintenance of normal renal function 75–78 cellular sites where these prostanoids are synthesized remain becomes dependent on prostanoids. COX inhibiting to be defined. non-steroidal anti-inflammatory drugs can cause a striking 75–78 A diverse family of membrane spanning G-protein decrease in GFR in these patients. Following the coupled prostanoid receptors has been cloned and character- discovery of the second isoform of COX, it was hypothesized ized. These include the D-prostanoid (DP), EP, F-prostanoid that the ‘house-keeping’ action of prostanoids were primarily (FP), I-prostanoid (IP), and T-prostanoid (TP) receptors, derived from COX1 pathway, and hoped that selective COX2 each of which selectively reacts with PGD2, PGE2, PGF2a, inhibitor would spare the renal hemodynamic effect of non- PGI2, or TxA2, respectively.31,32 Four subtypes of EP selective COX inhibitor. However, clinical studies have receptors have been cloned: EP1, EP2, EP3, and EP4.31,32 demonstrated that selective COX2 inhibition significantly Each prostanoid receptor activates a distinct G protein- reduces GFR and RBF in salt-depleted volunteers or 79–81 coupled signaling pathways. The IP, DP, EP2, and EP4 patients. The role of COX2-derived prostanoids in receptors are coupled to the stimulatory G-protein (Gs) and maintaining renal function has also been supported by 51,82 signal by increasing intracellular cyclic adenosine monophos- animal studies. The mechanism by which renal prosta- phate (cAMP) level, whereas the TP, FP, and EP1 receptors noids modulate renal hemodynamics has not been comple- induce calcium mobilization.31,32 The EP3 receptor is tely defined yet. Under volume-contracted conditions, coupled to an inhibitory G-protein (Gi) and reduces cAMP increased levels of catecholamines, angiotensin, and vaso- 83–85 synthesis.31,32 Although some of these receptors share the pressin act to constrict both renal and peripheral arteries. same second signaling pathway, the downstream targets of In the kidney, the effect of these vasoconstrictors is counter these second signaling pathways activated by each receptor balanced by vasodilators including prostanoids, preventing 86,87 could be different, leading to different physiological effect. RBF from falling. The receptors potentially mediating the The precise signaling mechanism underlying the effect of vasodilator effect of PGE2 and PGI2 include EP4, EP2, and IP 69,88 each prostanoid receptor has not been completely elucidated. receptors. Recent studies show that EP4 and EP2 receptor The intrarenal localization of these prostanoid receptors and agonists improve renal function and/or increase survival in the consequences of their activation have been only partially nephrotoxic mercury chloride rat model of acute renal 89 characterized.69 failure, consistent with protective role of COX-derived EP1 and EP3 mRNA expression predominates in the PGE2 in acute renal failure. collecting duct and thick limb, respectively, where their stimulation reduces NaCl and water absorption, promoting Renal prostanoids and blood pressure regulation natriuresis, and diuresis.69 The FP receptor is highly Prostanoids play an important role in modulating blood expressed in the distal convoluted tubule and collecting pressure.90,91 Inhibition of endogenous prostanoid synthesis duct, where it may exert distinct effects on renal salt by COX inhibiting non-steroidal anti-inflammatory drugs transport.70 Although only low levels of EP2 receptor mRNA may result in systemic hypertension or compromise the are detected in the kidney and its precise intrarenal control of blood pressure in subjects with pre-existing salt- localization is uncertain, mice with targeted disruption of sensitive hypertension.92–94 Recent clinical studies (including the EP2 receptor exhibit salt-sensitive hypertension, suggest- CLASS, VIGOR, TARGET, and APPROVe trials) show that ing that this receptor may play an important role in salt COX2 selective inhibition is also associated with hyperten- excretion.71,72 In contrast, EP4 receptor mRNA is predomi- sion.46,48,95–97 The mechanism by which COX2 inhibition nantly expressed in the glomerulus, where it may contribute causes hypertension is not completely understood. Adminis- to the regulation of glomerular hemodynamics and renin tration of selective COX2 or non-selective inhibitors to release.31,73 The IP receptor mRNA is highly expressed in the patients is frequently complicated by sodium retention and afferent arteriole, where it may also dilate renal arterioles and edema,48 suggesting that COX2-derived prostanoids are stimulate renin release.31 Conversely, TP receptor in the involved normally in modulating renal sodium excretion glomerulus may counteract the effects of these dilator and help maintain blood pressure. prostanoids and increase glomerular resistance. At present Renal medullary COX-derived prostanoids have been there is little evidence for DP receptor expression in the shown to play a critical role in modulating sodium kidney.31 homeostasis and maintaining blood pressure98 (Figure 2).

Kidney International (2007) 71, 1105–1115 1107 review C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators

EP4, EP2, or IP receptors.85,108–112 Gene knockout experi- Renin ments show that IP receptor gene disruption attenuates the development of hypertension in two-kidney one-clip hyper- tensive mouse model, accompanied by reduced plasma renin activity.106 However, deletion of EP2 or EP4 failed to reduce + blood pressure and renal renin release in the two-kidney one- clip mice.106 Other studies show that COX2 deletion is associated with reduced basal plasma renin concentration, which may contribute to reduced renin release following acute stimuli.113 More studies are required to elucidate the Na BP precise role of prostanoids in renal afferent arteriole renin – release. Figure 2 | Role of renal COX2 in blood pressure regulation. Critical role of COX2-derived prostanoids in renal development High-salt diet increases renal medullary COX2 expression.50 Reports of renal dysgenesis and oligohydramnios in offspring Selective inhibition of renal medullary COX2 via intrame- of women taken non-steroidal anti-inflammatory drugs dullary infusion of COX2 inhibitor causes rats on high salt during the third trimester of pregnancy have long implicated 50,51 diet to develop hypertension.47,99 COX2 inhibition is prostaglandins in the promotion of renal development. associated with reduced renal medullary blood flow,100 which This has been further confirmed by gene targeting studies in has been shown to be associated with sodium retention and mice. Targeted disruption of the COX2 gene but not the hypertension.101 The identity of the vasodilator effect of COX1 gene results in renal dysgenesis, characterized by prostanoid receptor controlling the contractile properties of hypoplastic glomeruli and loss of subcapsular tubules 34,36,52,53 the descending vasa recta that control renal medullary blood comprising the cortical mantle. Interestingly, it flow, remains uncertain, but EP2 and EP4 or IP receptors appears that COX2 activity is only required during the latter seem likely candidates.69,83 The importance of EP2 and IP phase of nephrogenesis, and in case of rodents, postnatal receptors in modulating sodium homeostasis and blood nephrogenesis. The cellular sites at which COX2 activity is pressure is supported by studies showing that EP2 or IP required for nephrogenesis are unknown. Nor is the cellular receptor deficiency is associated with salt-sensitive hyperten- mechanism by which COX2 activity promotes nephrogenesis sion.71,102 Several studies also indicate that EP1 receptor or known. In the developing kidney, COX2 expression is mainly EP3 receptor is responsible for the inhibitory effect of PGE2 detected in developing tubule epithelial cells adjacent to on salt absorption.103,104 However, despite these convincing nascent glomeruli and certain population of cells in comma- in vitro effects, genetic disruption of EP1 or EP3 by gene and S-shaped bodies, which appears to be the structure that 53,54 targeting does not cause salt retention or hypertension.69 develops into macula densa . Nevertheless, other studies In contrast to renal medullary COX2, renal cortical COX2 suggest expression of COX2 immuno-reactive protein in 54 activity is associated with renin release, and increases blood mesenchyme stromal cells during nephrogenesis. Thus the pressure (Figure 2). In settings of volume depletion, macula cellular source of COX2-derived prostanoids responsible for densa COX2 expression is dramatically increased.49,50 This kidney development remains to be elucidated. COX2 increase following low salt diet is associated with an increase in renin expression in the adjacent afferent Renal COX-derived prostanoids and diabetic nephropathy arteriole.105 COX2 inhibition or genetic knockout of COX2 Diabetic nephropathy is characterized by microalbuminuria, markedly attenuates low-salt diet-induced renin release.105 glomerular hypertrophy, mesangial expansion with glomer- These findings are consistent with a critical role for COX2- ular basement membrane thickening, arteriolar hyalinosis, derived prostaglandins in stimulating renin release and and global glomerular sclerosis, which ultimately lead to the maintaining blood pressure following extracellular volume progression to proteinuria and renal failure.114,115 Increased contraction. COX2-derived prostanoids have also been GFR (hyperfiltration) typifies the early stages of diabetic shown to mediate renin release caused by renal artery nephropathy.114,115 Animal studies show that in streptozotocin- stenosis, contributing to high renin renovascular hyperten- induced type I diabetic rats, renal PGE2, PGI2, and TxB2 sion.106,107 Animal studies showed that aorta coarctation or increase.116,117 COX2 expression is also increased in the thick renal artery clip is associated with increased renin release and ascending limb and macula densa in both type I strepto- hypertension, accompanied by increased cortical thick zotocin diabetic and type II diabetic Zucher rats.118–121 ascending limb/macula densa COX2 expression.107 COX2 Enhanced macula densa COX2 expression has also been inhibition has been shown to reduce renin activity and reported in human diabetic kidneys.122 Selective COX2 decrease blood pressure in rat with aortic coarctation.107 In inhibition significantly reduces glomerular hyperfiltration in vitro or ex vivo studies demonstrate that PGE2 and PGI2 can streptozotocin-induced diabetic rats, consistent with COX2- stimulate renin release from juxtaglomerular cells through derived prostanoids increasing RBF in the diabetic kidney.118

1108 Kidney International (2007) 71, 1105–1115 C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators review

The identity of these prostanoids and their cognate receptors LTE4) through leukotriene C4 synthase.126 LTC4 and LTD4 involved in pathogenesis of diabetic nephropathy has not contract vascular smooth muscle cells and increase vascular been completely characterized. Available data have shown permeability.128–130 LTB4 is a potent chemotactic substance that EP1 and EP3 receptor mRNA expression increases in the and increases polymorphonuclear leukocyte aggregation and kidney of streptozotocin-induced and genetic (Akita) type I adhesion to the endothelium.130 These leukotrienes are diabetic mice.123 EP1 receptor antagonist treatment amelio- usually released locally primarily by leukocytes. These rates renal and glomerular hypertrophy, and decreases properties of leukotrienes are consistent with their role in mesangial expansion.124 TP receptor antagonist has also been mediating inflammatory and allergic reactions.131–134 Mice reported to attenuate proteinuria and ameliorated histologi- with 5-LO gene disruption exhibit a reduced inflammatory cal changes of diabetic nephropathy in diabetic ApoE reaction, supporting the pro-inflammatory action of 5-LO (apolipoprotein E)-deficient mice.125 The role of COX- derived metabolites.127,135 derived prostanoids in pathogenesis of diabetic nephropathy 12-LO catalyzes the formation of oxidized lipids 12(S)- remains to be further explored. HETE. Human 15-LO type 1 shares high homolog with rodent leukocyte-type 12-LO; both can mediate the forma- LO-DERIVED EICOSANOIDS: 5-, 12-, AND 15-HETES AND tion of 12(S)-HETE and 15(S)-HETE from arachidonic acid, LEUKOTRIENES and are thus classified as 12/15-LO.126,127,136 The production Arachidonic acid can also be oxidized by LOs to form HETEs of 12(s)-HETE and 15(s)-HETE has been detected in and leukotrienes126,127(Figure 3). LOs are a family of non- vascular smooth muscle cells, endothelial cells, monocytes heme iron containing that insert molecular oxygen and platelet.137–140 Substantial evidence suggests that these into polyunsaturated fatty acids such as arachidonic acid and eicosanoids play important role in systemic homeostasis and .126 At least six functional human LOs have been renal-cardiovascular pathology.137–140 Recent studies indicate cloned: 5-LO (gene name: arachidonate lipoxygenase that 12/15-LO products are also involved in the pathogenesis (ALOX)5), platelet-type 12-LO (gene name: ALOX12), 12/ of atherosclerosis. 12/15-LO gene deletion is associated with 15-LO (leukocyte-type 12-LO for mice, 15-LO type 1 for reduced atherosclerosis in animal models.141–144 human, Gene name: ALOX15), epidermal-type 12-LO (gene name: ALOXE3), 12(R)-LO (gene name: ALOX12B), and Role of LO-derived products in glomerular injury 15-LO type 2 (8-lipoxygenase in mice, Gene name: 5-LO-derived products have been documented to play an ALOX15B).127 important role in mediating glomerular immune injury.88,145 5-LO is the key enzyme in leukotriene biosynthesis.127 5- 5-LO mRNA and 5-LOX-activating protein mRNA are lipoxygenase catalyzes the generation of leukotriene A4 in the detected in the glomeruli and vasa recta.146 Both leukotriene presence of 5-LO-activating protein. Leukotriene A4, in turn, receptor B4 and the cysteinyl leukotriene receptor type 1 are is converted by leukotriene A4 hydrolase to LTB4, capable of selectively expressed in the glomerulus.146 These studies activating LTB4 receptors. Leukotriene A4 can also be suggest that 5-LO products are involved in regulation of converted to cysteinyl (cys) leukotrienes (LTC4, LTD4, and glomerular function. Glomerular synthesis of LTB4 and

12-LO

OH 12(S)-HETE COOH COOH 15-LO

Arachidonic acid OH 15(S)-HETE O COOH OH OH 5-LO 1 COOH FLAP TLA4 2 OH TLB4 COOH

C5H11 S Cys Cly

TLC4 Gly OH COOH

C5H11 S Cys Cly TLD4 Figure 3 | Lipoxygenase pathway of arachidonic acid metabolism. (1) leukotriene A4 dydrolase; (2) Leukotriene C4 synthase.

Kidney International (2007) 71, 1105–1115 1109 review C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators

LTC4/LTD4 is markedly enhanced in the early course of 12-HETE and 15-HETE constrict renal vessels and glomer- several forms of glomerular immune injury, including ular mesangial cells.88,149 When infused into the renal artery, nephroxic serum nephritis, anti-thy1 nephritis, cationic 12-HETE decreases RBF and GFR.168 12(s)-HETE has also bovine g globulin-induced glomerular injury, and passive been shown to contribute to the afferent arteriolar response Heymann nephritis.145 LTD4 plays an important role in the to angiotensin.149 In summary, there is strong evidence that reduction of GFR in the acute phase of the injury by virtue of the LO system plays a key role in regulating renal function. its potent vasoconstrictor action and contraction of mesen- gial cells.145,147 LTD4 has also been reported to increase intra- CYTOCHROME P-450 MONOOXYGENASES DERIVED glomerular pressure, which may be associated with portei- EICOSANOIDS: 20-HETE AND EETs nuria.148 A 5-LO-activating protein antagonist has been Free arachidonic acid can also be oxidized by the cytochrome shown to reduce proteinuria in patients with glomerulone- P450 monooxygenase (CYP450) to produce hydroxy- and 5,169,170 phritis, supporting a role of leukotrienes in proteinuria.145 epoxy-arachidonic acid derivatives. The major LTB4, a potent promoter of polymorphonuclear leukocyte CYP450-catalyzed reactions in most tissues are mediated by attraction, participates in glomerular damage by amplifying epoxygenase and o-hydroxylase activities of the CYP450 polymorphonuclear leukocyte dependent mechanisms of family, which are responsible for biosynthesis of EETs and 20- 5,169,170 injury.147 HETE, respectively (Figure 4). Molecular biology studies have identified members of the P450 CYP2C and Role of LO-derived metabolites in pathogenesis of diabetic CYP4A gene subfamilies as functionally relevant epoxy- 169–172 nephropathy genases and o-hydroxylases, respectively. Accumulating evidence indicates that LO-derived products contribute to the pathogenesis of diabetic complications Effects of CYP P450-derived products on renal function including diabetic nephropathies.136 12/15-LO is detected in CYP450 monooxygenases are expressed in renal vascular and renal microvessels, glomeruli, and mesangial cells.149–151 12/ tubular structures and play diverse physiological and 88,169,173 15-LO levels are increased in the glomeruli of experimental pathophysiological functions. 20-HETE, a P450 diabetic animals.151–153 High glucose has been shown to hydroxylase-derived product, is a potent constrictor of renal 170,174–178 directly increase 12/15-LO expression in cultured mesangial arteries. The vasoconstrictor effects of 20-HETE cells.152 The 12/15 LO pathway has been shown to be a are mediated by blocking calcium-activated potassium 170,179 critical mediator of TGFb and ANG II-induced mesangial cell channel on vascular smooth muscle cells. Renal 20- hypertrophy and extracellular matrix accumulation.154–156 HETE has also been implicated in the vasoconstriction ANG II and TGFb treatment significantly increase 12-LO associated with activation of tubuloglomerular feedback and 180 mRNA expression and formation of the 12-LO product RBF autoregulation. 20-HETE also plays an important 12(S)-HETE in cultured rat mesangial cells.136 ANG II- role in the implementation of myogenic constrictor responses induced mesangial cell hypertrophy and extracellular matrix to elevation of transmural pressure in small renal arterial 175,181 synthesis in cultured rat mesangial cells can be blocked by an vessels. In the proximal tubule and in the thick LO inhibitor or targeted 12/15-LO gene deletion.136,154–156 ascending limb, 20-HETE is the primary metabolite of arachidonic acid.88,169,173 20-HETE has been shown to promote natriuresis by inhibiting Na þ /K þ -ATPase activity Role of LOs and their metabolites in regulating blood þ þ pressure in proximal tubule and inhibiting the Na -K -2Cl co- 173 Clinical studies in patients with essential hypertension, show transporter in thick ascending limb. EETs are produced urinary 12-HETE excretion is increased.157,158 A nonsynon- in the vascular endothelium by CYP2C and 2J family, and 88,169,170,173,179 ymous polymorphism in ALOX12, a gene encoding platelet- are potent vasodilators. EETs are also produced type 12-LO, is associated with essential hypertension.158 in tubules including the proximal tubule and collecting ducts 173,182 Increased 12-HETE production has also been reported in in the rodent kidney. EET has been shown to inhibit 183 animal models of hypertension such as spontaneous ENaC activity, which may contribute their natriuretic hypertensive rats and rats with renovascular hyperten- effect. EETs have also been shown to mediate natriuretic 169,184 sion.159–162 12-LO inhibitors have also been shown to effect of ANG II. ameliorate hypertension in these animals,162,163 and 12/15- LO gene deletion blunts the pressor response of ANG II.155 COOH These studies are consistent with an important role of 12-LO CH3 products in pathogenesis of hypertension. 12/15-LO defi- Arachidonic acid ciency is associated with increased endothelial nitric oxide AA epoxygenase AA ω/ω-1 hydroxygenase synthase (eNOS) expression and activity, suggesting 12/15- CYPs, 2C, 2J) CYPs 4A, 4F?) COOH COOH LO signaling contributes to altered NO bioactivity in vascular CH3 CH2OH 155 disease. 12-HETE also promotes vascular smooth muscle O 20-(or 19-, 18-, 17-, 16-) HETE cell proliferation,164–166 whereas 12/15-LO gene deletion 11, 12-(ror 5,6-, 8.9-, 14-, 15-) EET reduces vascular smooth muscle cell growth.167 In the kidney, Figure 4 | CYP450 pathway of arachidonic acid metabolism.

1110 Kidney International (2007) 71, 1105–1115 C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators review

Role of CYP450-derived arachidonic acid metabolites in O hypertension HN Substantial evidence indicates that CYP450 metabolites of O O H3C N P arachidonic acid play an important role in the pathogenesis H3C CH OO OH of hypertension. Renal expression of CYP4A2 and renal 3 Sphingomyelin production of 20-HETE are increased in spontaneous hypertensive rats.185–187 CYP450 inhibitors attenuate the Sphingomyelinase O development of hypertension in spontaneous hypertensive CAPP rats.187,188 CYP inhibitors have also been reported to prevent HN the development of hypertension in deoxycorticosterone HO CAPK 173 acetate (DOCA) salt and ANG II-induced hypertension. OH Ceramide PKCzeta Interestingly, targeted deletion of cyp4a14 in mice is 189 Ceramide Ceramidase associated with hypertension. Further studies shows that synthase cyp4a14 deletion increases renal expression of cyp4a12, HN resulting in increase in renal 20-HETE synthesis, and blood HO pressure,189 consistent with the pro-hypertensive effect of 20- OH HETE. Cpy4a14-deficiency-induced cyp4a12 expression and Sphingsine 189 hypertension is androgen dependent. Clinical studies show Figure 5 | Ceramide biosynthesis. T8590C polymorphism of CYP4A11, a human ortholog of murine 4a14, is also associated with hypertension.190,191 The mechanism underlying this association of the polymorphism signaling molecules have been demonstrated to be responsive of CYP4A11 and hypertension remains to be defined. to cellular ceramide levels, including Raf-1, mitogen- P450 epoxygenase products appear to have antihyperten- activated protein kinase, arachidonic acid, c-myc, the sive effect, probably via their vasodilator effect and retinoblastoma gene products, and IkB.194 Ceramide synth- 88,169 natriuretic effect. In rats, high-salt diet induces epox- esis can be induced by 1,25(OH)2 VitD3, tumor necrosis ygenase activity and markedly increases the urinary levels of factor a, endotoxin, interferon g, IL-1, retinoic acid, 184 its metabolites. Epoxygenase inhibition is associated with progesterone, and ionizing irradiation.193 Numerous stresses 192 salt sensitive hypertension. Furthermore, high-salt diet that initiate apoptosis have been associated with rapid induces renal epoxygenase in normotensive Dahl salt- ceramide generation, including ionizing radiation, heat resistant rats but not in hypertensive Dahl salt-sensitive rats, shock, oxidative stress, daunorubicin, and vincristine, con- consistent with antihypertensive effect of epoxygenase sistent with critical role of ceramide in apoptosis.195 192 derived products following high-salt diet. Importantly, It has been documented that ceramide is involved in deletion of mouse cyp4a10, another member of cyp4a family, pathogenesis of acute kidney injury caused by ischemia/ causes salt-sensitive hypertension rather than gender-depen- reperfusion, toxic insults, and oxidative stress.196–199 In 183 dent hypertension as seen with cyp4a14 deficiency. normal mouse kidney cortex, C24, C22 and C16 ceramides Cyp4a10 gene disruption is associated with reduced urinary have been identified.200 Ischemia/reperfusion or nephrotoxic 183 EET excretion, and induction of cyp2c expression and injury (glycerol-mediated myohemoglobinuria, radiocon- EETs synthesis with a PPARa , attenuates cyp4a10 trast) causes a transient reduction of renal ceramide levels, 183 deficiency-induced salt-sensitive hypertension. These stu- followed by a 2–3 fold of increase in ceramide levels.199,201,202 dies support an antihypertensive effect of cyp2c-derived EETs The increased ceramide after renal injury does not seem to be following high-salt diet. associated with enhanced hydrolysis of sphingomyelin, as sphingomyelinase expression is not increased but rather 198 ROLE OF SPHINGOMYELIN AND CERAMIDE IN THE NORMAL reduced throughout the experiments. In contrast, hypoxia- AND DISEASED KIDNEY reoxygenation or radiocontrast-induced renal tubular epithe- Ceramide is also an important signaling molecule, playing an lial cell injury is attenuated by the ceramide synthase important role in cellular responses to stress, cell growth and inhibitor, fumonisin B1, suggesting that increased ceramide differentiation, and apoptosis.193–195 Ceramide is produced synthase activity is responsible for increased ceramide mainly from the hydrolysis of sphingomyelin catalyzed by generation, leading to apoptotic change of the renal epithelial sphingomyelinase193,194 (Figure 5). Ceramide can also been cells.202,203 Of interest, recent studies in mesangial cells show generated through condensation of sphingosine or sphinga- that ceramide mediates enhanced collagen synthesis in nine and fatty acyl-CoA by ceramide synthase195 (Figure 5). response to homocysteine, which has been documented to The direct targets of ceramide include ceramide-activated play an important role in glomerular sclerosis.204 protein phosphatase, ceramide-activated protein kinase, and protein kinase Cz. The ceramide-activated protein phospha- SUMMARY tase is related to PPA2 family of phosphatase, and can be Eicosanoids exert diverse and complex functions. The specific inhibited by okadaic acid.193 A number of intracellular effect of each eicosanoid depends on sequential enzymatic

Kidney International (2007) 71, 1105–1115 1111 review C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators

machinery in a specific cell, yielding a specific eicosanoid, 22. Cybulsky AV, Takano T, Papillon J et al. The actin cytoskeleton facilitates complement-mediated activation of cytosolic phospholipase A2. Am J exerting its distinct function. The biosynthesis of each Physiol Renal Physiol 2004; 286: F466–F476. eicosanoid is regulated at multiple levels from phospholipase 23. Petry C, Huwiler A, Eberhardt W et al. Hypoxia increases group IIA A2 that catalyzes the release of arachidonic acid to specific phospholipase A(2) expression under inflammatory conditions in rat renal mesangial cells. J Am Soc Nephrol 2005; 16: 2897–2905. enzymes that catalyze the formation of bioactive eicosanoids. 24. Alexander LD, Alagarsamy S, Douglas JG. Cyclic stretch-induced cPLA2 Arachidonate derived eicosanoids including prostanoids, mediates ERK 1/2 signaling in rabbit proximal tubule cells. Kidney Int 2004; 65: 551–563. leukotrienes, 12/15-HETEs, EETs, and HETEs, and sphingo- 25. Sapirstein A, Spech RA, Witzgall R et al. Cytosolic phospholipase A2 myelin-derived ceramide play important roles in maintaining (PLA2), but not secretory PLA2, potentiates hydrogen peroxide normal renal function. They are also involved in the cytotoxicity in kidney epithelial cells. J Biol Chem 1996; 271: 21505–21513. pathophysiology of hypertension, diabetic nephropathy, and 26. Sheridan AM, Force T, Yoon HJ et al. PLIP, a novel splice variant of Tip60, inflammatory or toxic glomerular injury. Those signaling interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and pathways should provide fruitful targets for intervention in potentiates prostaglandin production. Mol Cell Biol 2001; 21: 4470–4481. 27. Boyanovsky BB, van der Westhuyzen DR, Webb NR. Group V secretory the pharmacologic treatment of renal disease. phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves REFERENCES cellular proteoglycans. J Biol Chem 2005; 280: 32746–32752. 1. Brash AR. Arachidonic acid as a bioactive molecule. J Clin Invest 2001; 28. Fuentes L, Hernandez M, Fernandez-Aviles FJ et al. Cooperation 107: 1339–1345. between secretory phospholipase A2 and TNF-receptor superfamily 2. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid signaling: implications for the inflammatory response in atherogenesis. biology. Science 2001; 294: 1871–1875. Circ Res 2002; 91: 681–688. 3. Fitzpatrick FA, Soberman R. Regulated formation of eicosanoids. J Clin 29. Murakami M, Kudo I. New phospholipase A(2) isozymes with a potential Invest 2001; 107: 1347–1351. role in atherosclerosis. Curr Opin Lipidol 2003; 14: 431–436. 4. FitzGerald GA, Loll P. COX in a crystal ball: current status and future 30. Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta 1996; promise of prostaglandin research. J Clin Invest 2001; 107: 1335–1337. 1299: 125–140. 5. Capdevila JH, Harris RC, Falck JR. Microsomal cytochrome P450 and 31. Breyer MD, Breyer RM. Prostaglandin receptors: their role in regulating eicosanoid metabolism. Cell Mol Life Sci 2002; 59: 780–789. renal function. Curr Opin Nephrol Hypertens 2000; 9: 23–29. 6. Smith WL. Prostanoid biosynthesis and mechanisms of action. Am J 32. Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of Physiol 1992; 263: F181–F191. prostanoid receptor function. J Clin Invest 2001; 108: 25–30. 7. Hla T, Bishop-Bailey D, Liu CH et al. Cyclooxygenase-1 and -2 33. Hao CM, Redha R, Morrow J et al. Peroxisome proliferator-activated isoenzymes. Int J Biochem Cell Biol 1999; 31: 551–557. receptor delta activation promotes cell survival following hypertonic 8. Bonventre JV. The 85-kD cytosolic phospholipase A2 knockout mouse: a stress. J Biol Chem 2002; 277: 21341–21345. new tool for physiology and cell biology. J Am Soc Nephrol 1999; 10: 34. Lim H, Dey SK. PPAR delta functions as a prostacyclin receptor in 404–412. blastocyst implantation. Trends Endocrinol Metab 2000; 11: 137–142. 9. Kudo I, Murakami M. Phospholipase A2 enzymes. Prostaglandins Other 35. Bernardo A, Levi G, Minghetti L. Role of the peroxisome Lipid Mediat 2002; 68–69: 3–58. proliferator-activated receptor-gamma (PPAR-gamma) and its natural 10. Shimizu T, Ohto T, Kita Y. Cytosolic phospholipase A2: biochemical ligand 15-deoxy-Delta12, 14-prostaglandin J2 in the regulation of properties and physiological roles. IUBMB Life 2006; 58: 328–333. microglial functions. Eur J Neurosci 2000; 12: 2215–2223. 11. Clark JD, Lin LL, Kriz RW et al. A novel arachidonic acid-selective 36. Ward JE, Gould H, Harris T et al. PPAR gamma ligands, 15-deoxy-delta12, cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with 14-prostaglandin J2 and rosiglitazone regulate human cultured airway homology to PKC and GAP. Cell 1991; 65: 1043–1051. smooth muscle proliferation through different mechanisms. Br J 12. Clark JD, Milona N, Knopf JL. Purification of a 110-kilodalton cytosolic Pharmacol 2004; 141: 517–525. phospholipase A2 from the human monocytic cell line U937. Proc Natl 37. Simmons DL, Levy DB, Yannoni Y et al. Identification of a phorbol Acad Sci USA 1990; 87: 7708–7712. ester-repressible v-src-inducible gene. Proc Natl Acad Sci USA 1989; 86: 13. Sharp JD, White DL, Chiou XG et al. Molecular cloning and expression of 1178–1182. human Ca(2+)-sensitive cytosolic phospholipase A2. J Biol Chem 1991; 38. Guan Y, Chang M, Cho W et al. Cloning, expression, and regulation of 266: 14850–14853. rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol 14. Barnett RL, Ruffini L, Hart D et al. Mechanism of endothelin activation of 1997; 273: F18–F26. phospholipase A2 in rat renal medullary interstitial cells. Am J Physiol 39. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 1994; 266: F46–F56. 1992; 89: 7384–7388. 15. Resink TJ, Scott-Burden T, Buhler FR. Activation of phospholipase A2 by 40. Kujubu DA, Fletcher BS, Varnum BC et al. TIS10, a phorbol ester tumor endothelin in cultured vascular smooth muscle cells. Biochem Biophys promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel Res Commun 1989; 158: 279–286. prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991; 16. Schramek H, Wang Y, Konieczkowski M et al. Endothelin-1 stimulates 266: 12866–12872. cytosolic phospholipase A2 activity and in rat 41. Smith WL, Langenbach R. Why there are two cyclooxygenase isozymes. glomerular mesangial cells. Kidney Int 1994; 46: 1644–1652. J Clin Invest 2001; 107: 1491–1495. 17. Takakuwa T, Endo S, Nakae H et al. Relationship between plasma levels 42. Dinchuk JE, Car BD, Focht RJ et al. Renal abnormalities and an altered of type II phospholipase A2, PAF acetylhydrolase, endothelin-1, and inflammatory response in mice lacking cyclooxygenase II. Nature 1995; thrombomodulin in patients with infected burns. Res Commun Mol 378: 406–409. Pathol Pharmacol 1994; 86: 335–340. 43. Morham SG, Langenbach R, Loftin CD et al. Prostaglandin synthase 2 18. Dulin NO, Alexander LD, Harwalkar S et al. Phospholipase A2-mediated gene disruption causes severe renal pathology in the mouse. Cell 1995; activation of mitogen-activated protein kinase by angiotensin II. Proc 83: 473–482. Natl Acad Sci USA 1998; 95: 8098–8102. 44. Komhoff M, Wang JL, Cheng HF et al. Cyclooxygenase-2-selective 19. Lehman JJ, Brown KA, Ramanadham S et al. Arachidonic acid release inhibitors impair glomerulogenesis and renal cortical development. from aortic smooth muscle cells induced by [Arg8]vasopressin is largely Kidney Int 2000; 57: 414–422. mediated by calcium-independent phospholipase A2. J Biol Chem 1993; 45. Lim H, Paria BC, Das SK et al. Multiple female reproductive failures in 268: 20713–20716. cyclooxygenase 2-deficient mice. Cell 1997; 91: 197–208. 20. Liu Y, Taylor CW. Stimulation of arachidonic acid release by vasopressin 46. Bresalier RS, Sandler RS, Quan H et al. Cardiovascular events associated in A7r5 vascular smooth muscle cells mediated by Ca2+-stimulated with in a colorectal adenoma chemoprevention trial. N Engl phospholipase A2. FEBS Lett 2006; 580: 4114–4120. JMed2005; 352: 1092–1102. 21. Goto S, Nakamura H, Morooka H et al. Role of reactive oxygen in 47. Zewde T, Mattson DL. Inhibition of cyclooxygenase-2 in the rat renal phospholipase A2 activation by ischemia/reperfusion of the rat kidney. medulla leads to sodium-sensitive hypertension. Hypertension 2004; 44: J Anesth 1999; 13: 90–93. 424–428.

1112 Kidney International (2007) 71, 1105–1115 C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators review

48. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors 75. Arisz L, Donker AJ, Brentjens JR et al. The effect of indomethacin on on renal and arrhythmia events: meta-analysis of randomized trials. proteinuria and kidney function in the nephrotic syndrome. Acta Med JAMA 2006; 296: 1619–1632. Scand 1976; 199: 121–125. 49. Harris RC, McKanna JA, Akai Y et al. Cyclooxygenase-2 is associated with 76. Walshe JJ, Brentjens JR, Costa GG et al. Abdominal pain associated with the macula densa of rat kidney and increases with salt restriction. J Clin IgA nephropathy. Possible mechanism. Am J Med 1984; 77: 765–767. Invest 1994; 94: 2504–2510. 77. Antillon M, Cominelli F, Lo S et al. Effects of oral prostaglandins on 50. Yang T, Singh I, Pham H et al. Regulation of cyclooxygenase expression indomethacin-induced renal failure in patients with cirrhosis and ascites. in the kidney by dietary salt intake. Am J Physiol 1998; 274: F481–F489. J Rheumatol Suppl 1990; 20: 46–49. 51. Castrop H, Schweda F, Schumacher K et al. Role of renocortical 78. Huerta C, Rodriguez LA. Incidence of ocular melanoma in the general cyclooxygenase-2 for renal vascular resistance and macula densa control population and in glaucoma patients. J Epidemiol Community Health of renin secretion. J Am Soc Nephrol 2001; 12: 867–874. 2001; 55: 338–339. 52. Hao CM, Komhoff M, Guan Y et al. Selective targeting of 79. Rossat J, Maillard M, Nussberger J et al. Renal effects of selective cyclooxygenase-2 reveals its role in renal medullary interstitial cell cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. survival. Am J Physiol 1999; 277: F352–F359. Clin Pharmacol Ther 1999; 66: 76–84. 53. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin 80. Catella-Lawson F, McAdam B, Morrison BW et al. Effects of specific inhibition in human disease. Nat Rev Drug Discov 2003; 2: 879–890. inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and 54. Jakobsson PJ, Thoren S, Morgenstern R et al. Identification of human vasoactive eicosanoids. J Pharmacol Exp Ther 1999; 289: 735–741. prostaglandin E synthase: a microsomal, glutathione-dependent, 81. Swan SK, Rudy DW, Lasseter KC et al. Effect of cyclooxygenase-2 inducible enzyme, constituting a potential novel drug target. Proc Natl inhibition on renal function in elderly persons receiving a low-salt diet. Acad Sci USA 1999; 96: 7220–7225. A randomized, controlled trial. Ann Intern Med 2000; 133:1–9. 55. Tanioka T, Nakatani Y, Semmyo N et al. Molecular identification of 82. Rodriguez F, Llinas MT, Gonzalez JD et al. Renal changes induced by a cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-2 inhibitor during normal and low sodium intake. cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Hypertension 2000; 36: 276–281. Chem 2000; 275: 32775–32782. 83. Breyer MD, Hao C, Qi Z. Cyclooxygenase-2 selective inhibitors and the 56. Tanikawa N, Ohmiya Y, Ohkubo H et al. Identification and kidney. Curr Opin Crit Care 2001; 7: 393–400. characterization of a novel type of membrane-associated prostaglandin 84. Pinilla JM, Alberola A, Gonzalez JD et al. Role of prostaglandins on the E synthase. Biochem Biophys Res Commun 2002; 291: 884–889. renal effects of angiotensin and interstitial pressure during volume 57. Lazarus M, Kubata BK, Eguchi N et al. Biochemical characterization of expansion. Am J Physiol 1993; 265: R1469–R1474. mouse microsomal prostaglandin E synthase-1 and its colocalization 85. Ito S, Carretero OA, Abe K et al. Effect of prostanoids on renin release with cyclooxygenase-2 in peritoneal macrophages. Arch Biochem from rabbit afferent arterioles with and without macula densa. Kidney Int Biophys 2002; 397: 336–341. 1989; 35: 1138–1144. 58. Murakami M, Nakatani Y, Tanioka T et al. Prostaglandin E synthase. 86. Mzail AH, Noble AR. Haemorrhage-induced secretion of active and Prostaglandins Other Lipid Mediat 2002; 68–69: 383–399. inactive renin in conscious and pentobarbitone-anaesthetized sheep. 59. Urade Y, Eguchi N. Lipocalin-type and hematopoietic prostaglandin D Clin Exp Pharmacol Physiol 1986; 13: 131–138. synthases as a novel example of functional convergence. Prostaglandins 87. Yared A, Kon V, Ichikawa I. Mechanism of preservation of glomerular Other Lipid Mediat 2002; 68–69: 375–382. perfusion and filtration during acute extracellular fluid volume 60. Urade Y, Hayaishi O. Biochemical, structural, genetic, physiological, and depletion. Importance of intrarenal vasopressin-prostaglandin pathophysiological features of lipocalin-type prostaglandin D synthase. interaction for protecting kidneys from constrictor action of vasopressin. Biochim Biophys Acta 2000; 1482: 259–271. J Clin Invest 1985; 75: 1477–1487. 61. Watanabe K. Prostaglandin F synthase. Prostaglandins Other Lipid Mediat 88. Imig JD. Eicosanoids and renal vascular function in diseases. Clin Sci 2002; 68–69: 401–407. (London) 2006; 111: 21–34. 62. Lee SC, Levine L. Purification and regulatory properties of chicken 89. Vukicevic S, Simic P, Borovecki F et al. Role of EP2 and EP4 receptor- heart prostaglandin E 9-ketoreductase. J Biol Chem 1975; 250: selective agonists of prostaglandin E(2) in acute and chronic kidney 4549–4555. failure. Kidney Int 2006; 70: 1099–1106. 63. Westbrook C, Jarabak J. Purification and partial characterization of an 90. Anderson RJ, Berl T, McDonald KM et al. Prostaglandins: effects on blood NADH-linked delta13–15-ketoprostaglandin reductase from human pressure, renal blood flow, sodium and water excretion. Kidney Int 1976; placenta. Biochem Biophys Res Commun 1975; 66: 541–546. 10: 205–215. 64. Schneider A, Zhang Y, Zhang M et al. Membrane-associated PGE 91. Daniels EG, Hinman JW, Leach BE et al. Identification of prostaglandin E2 synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the as the principal vasodepressor lipid of rabbit renal medulla. Nature 1967; kidney. Kidney Int 2004; 65: 1205–1213. 215: 1298–1299. 65. Vitzthum H, Abt I, Einhellig S et al. Gene expression of prostanoid 92. Fierro-Carrion GA, Ram CV. Nonsteroidal anti-inflammatory drugs forming enzymes along the rat nephron. Kidney Int 2002; 62: 1570–1581. (NSAIDs) and blood pressure. Am J Cardiol 1997; 80: 775–776. 66. Yang G, Chen L, Zhang Y et al. Expression of mouse membrane- 93. Jackson EK. Relation between renin release and blood pressure response associated prostaglandin E(2) synthase-2 (mPGES-2) along the to nonsteroidal anti-inflammatory drugs in hypertension. Hypertension urogenital tract. Biochim Biophys Acta 2006; 1761: 1459–1468. 1989; 14: 469–471. 67. Zhang Y, Schneider A, Rao R et al. Genomic structure and genitourinary 94. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of expression of mouse cytosolic prostaglandin E(2) synthase gene. nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Biochim Biophys Acta 2003; 1634: 15–23. Med 1993; 153: 477–484. 68. Qi Z, Cai H, Morrow JD et al. Differentiation of cyclooxygenase 1- and 95. Bombardier C, Laine L, Reicin A et al. Comparison of upper 2-derived prostanoids in mouse kidney and aorta. Hypertension 2006; gastrointestinal toxicity of rofecoxib and in patients with 48: 323–328. rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343: 69. Breyer MD, Breyer RM. G protein-coupled prostanoid receptors and the 1520–1528, 1522 p following 1528. kidney. Annu Rev Physiol 2001; 63: 579–605. 96. Farkouh ME, Kirshner H, Harrington RA et al. Comparison of 70. Saito O, Guan Y, Qi Z et al. Expression of the prostaglandin F receptor with naproxen and in the Therapeutic Arthritis Research and (FP) gene along the mouse genitourinary tract. Am J Physiol Renal Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: Physiol 2003; 284: F1164–F1170. randomised controlled trial. Lancet 2004; 364: 675–684. 71. Kennedy CR, Zhang Y, Brandon S et al. Salt-sensitive hypertension and 97. Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat Med vs nonsteroidal anti-inflammatory drugs for osteoarthritis and 1999; 5: 217–220. rheumatoid arthritis: the CLASS study: A randomized controlled 72. Tilley SL, Audoly LP, Hicks EH et al. Reproductive failure and reduced trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: blood pressure in mice lacking the EP2 prostaglandin E2 receptor. J Clin 1247–1255. Invest 1999; 103: 1539–1545. 98. Muirhead EE. Renal vasodepressor mechanisms: the medullipin system. 73. Breyer RM, Davis LS, Nian C et al. Cloning and expression of the rabbit J Hypertens Suppl 1993; 11(Suppl 5): S53–S58. prostaglandin EP4 receptor. Am J Physiol 1996; 270: F485–F493. 99. Ye W, Zhang H, Hillas E et al. Expression and function of COX isoforms in 74. DiBona GF. Prostaglandins and nonsteroidal anti-inflammatory drugs. renal medulla: evidence for regulation of salt sensitivity and blood Effects on renal hemodynamics. Am J Med 1986; 80: 12–21. pressure. Am J Physiol Renal Physiol 2006; 290: F542–F549.

Kidney International (2007) 71, 1105–1115 1113 review C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators

100. Qi Z, Hao CM, Langenbach RI et al. Opposite effects of cyclooxygenase-1 127. Funk CD, Chen XS, Johnson EN et al. Lipoxygenase and their and -2 activity on the pressor response to angiotensin II. J Clin Invest targeted disruption. Prostaglandins Other Lipid Mediat 2002; 68–69: 2002; 110: 61–69. 303–312. 101. Bergstrom G, Evans RG. Mechanisms underlying the antihypertensive 128. Lewis RA, Austen KF. Molecular determinants for functional responses to functions of the renal medulla. Acta Physiol Scand 2004; 181: 475–486. the sulfidopeptide leukotrienes: metabolism and receptor subclasses. 102. Francois H, Athirakul K, Howell D et al. Prostacyclin protects against J Allergy Clin Immunol 1984; 74: 369–372. elevated blood pressure and cardiac fibrosis. Cell Metab 2005; 2: 129. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of 201–207. the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology 103. Guan Y, Zhang Y, Breyer RM et al. Prostaglandin E2 inhibits renal in human diseases. N Engl J Med 1990; 323: 645–655. collecting duct Na+ absorption by activating the EP1 receptor. J Clin 130. Samuelsson B, Dahlen SE, Lindgren JA et al. Leukotrienes and lipoxins: Invest 1998; 102: 194–201. structures, biosynthesis, and biological effects. Science 1987; 237: 104. Hebert RL, Jacobson HR, Fredin D et al. Evidence that separate PGE2 1171–1176. receptors modulate water and sodium transport in rabbit cortical 131. Steinhilber D. 5-Lipoxygenase: a target for antiinflammatory drugs collecting duct. Am J Physiol 1993; 265: F643–F650. revisited. Curr Med Chem 1999; 6: 71–85. 105. Cheng HF, Wang JL, Zhang MZ et al. Genetic deletion of COX-2 prevents 132. Funk CD, Chen XS. 5-Lipoxygenase and leukotrienes. Transgenic mouse increased renin expression in response to ACE inhibition. Am J Physiol and nuclear targeting studies. Am J Respir Crit Care Med 2000; 161: Renal Physiol 2001; 280: F449–F456. S120–S124. 106. Fujino T, Nakagawa N, Yuhki K et al. Decreased susceptibility to 133. Mehrabian M, Allayee H. 5-lipoxygenase and atherosclerosis. Curr Opin renovascular hypertension in mice lacking the prostaglandin I2 receptor Lipidol 2003; 14: 447–457. IP. J Clin Invest 2004; 114: 805–812. 134. Werz O. 5-Lipoxygenase: cellular biology and molecular pharmacology. 107. Wang JL, Cheng HF, Harris RC. Cyclooxygenase-2 inhibition decreases Curr Drug Targets Inflamm Allergy 2002; 1: 23–44. renin content and lowers blood pressure in a model of renovascular 135. Chen XS, Sheller JR, Johnson EN et al. Role of leukotrienes revealed by hypertension. Hypertension 1999; 34: 96–101. targeted disruption of the 5-lipoxygenase gene. Nature 1994; 372: 108. Traynor TR, Smart A, Briggs JP et al. Inhibition of macula densa- 179–182. stimulated renin secretion by pharmacological blockade of 136. Natarajan R, Nadler JL. Lipid inflammatory mediators in diabetic vascular cyclooxygenase-2. Am J Physiol 1999; 277: F706–F710. disease. Arterioscler Thromb Vasc Biol 2004; 24: 1542–1548. 109. Vander AJ. Direct effects of prostaglandin on renal function and renin 137. Dailey LA, Imming P. 12-Lipoxygenase: classification, possible release in anesthetized dog. Am J Physiol 1968; 214: 218–221. therapeutic benefits from inhibition, and inhibitors. Curr Med Chem 110. Jensen BL, Schmid C, Kurtz A. Prostaglandins stimulate renin secretion 1999; 6: 389–398. and renin mRNA in mouse renal juxtaglomerular cells. Am J Physiol 1996; 138. Spokas EG, Rokach J, Wong PY. Leukotrienes, lipoxins, and 271: F659–F669. hydroxyeicosatetraenoic acids. Methods Mol Biol 1999; 120: 111. Friis UG, Stubbe J, Uhrenholt TR et al. Prostaglandin E2 EP2 and EP4 213–247. receptor activation mediates cAMP-dependent hyperpolarization and 139. Tang K, Honn KV. Lipoxygenase metabolites and cancer metastasis. exocytosis of renin in juxtaglomerular cells. Am J Physiol Renal Physiol Adv Exp Med Biol 1997; 422: 71–84. 2005; 289: F989–F997. 140. Zhao L, Funk CD. Lipoxygenase pathways in atherogenesis. Trends 112. Schweda F, Klar J, Narumiya S et al. Stimulation of renin release by Cardiovasc Med 2004; 14: 191–195. prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse 141. Cyrus T, Pratico D, Zhao L et al. Absence of 12/15-lipoxygenase kidneys. Am J Physiol Renal Physiol 2004; 287: F427–F433. expression decreases lipid peroxidation and atherogenesis in 113. Kim SM, Chen L, Mizel D et al. Low plasma renin and reduced renin apolipoprotein e-deficient mice. Circulation 2001; 103: 2277–2282. secretory responses to acute stimuli in conscious COX-2-deficient mice. 142. Cyrus T, Witztum JL, Rader DJ et al. Disruption of the 12/15-lipoxygenase Am J Physiol Renal Physiol 2007; 292: F415–F422. gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest 114. Breyer MD, Bottinger E, Brosius FC et al. Diabetic nephropathy: of mice 1999; 103: 1597–1604. and men. Adv Chronic Kidney Dis 2005; 12: 128–145. 143. Reddy MA, Kim YS, Lanting L et al. Reduced growth factor responses in 115. McGowan T, McCue P, Sharma K. Diabetic nephropathy. Clin Lab Med vascular smooth muscle cells derived from 12/15-lipoxygenase-deficient 2001; 21: 111–146. mice. Hypertension 2003; 41: 1294–1300. 116. Craven PA, Caines MA, DeRubertis FR. Sequential alterations in 144. Zhao L, Cuff CA, Moss E et al. Selective interleukin-12 synthesis defect in glomerular prostaglandin and thromboxane synthesis in diabetic rats: 12/15-lipoxygenase-deficient macrophages associated with reduced relationship to the hyperfiltration of early diabetes. Metabolism 1987; atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol 36: 95–103. Chem 2002; 277: 35350–35356. 117. Moel DI, Safirstein RL, McEvoy RC et al. Effect of on experimental 145. Badr KF. Lipoxygenases as therapeutic targets in the acute and subacute diabetic nephropathy. J Lab Clin Med 1987; 110: 300–307. phases of glomerular immune injury. Contrib Nephrol 1996; 118: 118. Komers R, Lindsley JN, Oyama TT et al. Immunohistochemical and 113–125. functional correlations of renal cyclooxygenase-2 in experimental 146. Reinhold SW, Vitzthum H, Filbeck T et al. Gene expression of 5-, 12-, and diabetes. J Clin Invest 2001; 107: 889–898. 15-lipoxygenases and leukotriene receptors along the rat nephron. Am 119. Cheng HF, Wang CJ, Moeckel GW et al. Cyclooxygenase-2 inhibitor J Physiol Renal Physiol 2006; 290: F864–F872. blocks expression of mediators of renal injury in a model of diabetes 147. Badr KF. Five-lipoxygenase products in glomerular immune injury. JAm and hypertension. Kidney Int 2002; 62: 929–939. Soc Nephrol 1992; 3: 907–915. 120. Dey A, Williams RS, Pollock DM et al. Altered kidney CYP2C and 148. Katoh T, Lianos EA, Fukunaga M et al. Leukotriene D4 is a mediator of cyclooxygenase-2 levels are associated with obesity-related albuminuria. proteinuria and glomerular hemodynamic abnormalities in passive Obes Res 2004; 12: 1278–1289. Heymann nephritis. J Clin Invest 1993; 91: 1507–1515. 121. Komers R, Zdychova J, Cahova M et al. Renal cyclooxygenase-2 in obese 149. Yiu SS, Zhao X, Inscho EW et al. 12-Hydroxyeicosatetraenoic acid Zucker (fatty) rats. Kidney Int 2005; 67: 2151–2158. participates in angiotensin II afferent arteriolar vasoconstriction by 122. Khan KN, Stanfield KM, Harris RK et al. Expression of cyclooxygenase-2 in activating L-type calcium channels. J Lipid Res 2003; 44: 2391–2399. the macula densa of human kidney in hypertension, congestive heart 150. Gonzalez-Nunez D, Sole M, Natarajan R et al. 12-Lipoxygenase failure, and diabetic nephropathy. Ren Fail 2001; 23: 321–330. metabolism in mouse distal convoluted tubule cells. Kidney Int 2005; 67: 123. Nasrallah R, Xiong H, Hebert RL. Renal prostaglandin E2 receptor (EP) 178–186. expression profile is altered in streptozotocin and B6-Ins2Akita type I- 151. Xu ZG, Li SL, Lanting L et al. Relationship between 12/15-lipoxygenase diabetic mice. Am J Physiol Renal Physiol 2006; 292: F278–F284. and COX-2 in mesangial cells: potential role in diabetic nephropathy. 124. Makino H, Tanaka I, Mukoyama M et al. Prevention of diabetic Kidney Int 2006; 69: 512–519. nephropathy in rats by prostaglandin E receptor EP1-selective 152. Kang SW, Adler SG, Nast CC et al. 12-lipoxygenase is increased in antagonist. J Am Soc Nephrol 2002; 13: 1757–1765. glucose-stimulated mesangial cells and in experimental diabetic 125. Xu S, Jiang B, Maitland KA et al. The thromboxane receptor antagonist nephropathy. Kidney Int 2001; 59: 1354–1362. S18886 attenuates renal oxidant stress and proteinuria in diabetic 153. Antonipillai I, Nadler J, Vu EJ et al. A 12-lipoxygenase product, apolipoprotein E-deficient mice. Diabetes 2006; 55: 110–119. 12-hydroxyeicosatetraenoic acid, is increased in diabetics with 126. Brash AR. Lipoxygenases: occurrence, functions, catalysis, and incipient and early renal disease. J Clin Endocrinol Metab 1996; 81: acquisition of substrate. J Biol Chem 1999; 274: 23679–23682. 1940–1945.

1114 Kidney International (2007) 71, 1105–1115 C-M Hao and MD Breyer: Physiologic and pathophysiologic roles in lipid mediators review

154. Kim YS, Xu ZG, Reddy MA et al. Novel interactions between TGF-{beta}1 180. Zou AP, Imig JD, Ortiz de Montellano PR et al. Effect of P-450 omega- actions and the 12/15-lipoxygenase pathway in mesangial cells. JAm hydroxylase metabolites of arachidonic acid on tubuloglomerular Soc Nephrol 2005; 16: 352–362. feedback. Am J Physiol 1994; 266: F934–F941. 155. Anning PB, Coles B, Bermudez-Fajardo A et al. Elevated endothelial nitric 181. Kauser K, Clark JE, Masters BS et al. Inhibitors of cytochrome P-450 oxide bioactivity and resistance to angiotensin-dependent hypertension attenuate the myogenic response of dog renal arcuate arteries. Circ Res in 12/15-lipoxygenase knockout mice. Am J Pathol 2005; 166: 653–662. 1991; 68: 1154–1163. 156. Kim YS, Reddy MA, Lanting L et al. Differential behavior of mesangial 182. Wei Y, Lin DH, Kemp R et al. Arachidonic acid inhibits epithelial Na cells derived from 12/15-lipoxygenase knockout mice relative to control channel via cytochrome P450 (CYP) epoxygenase-dependent metabolic mice. Kidney Int 2003; 64: 1702–1714. pathways. J Gen Physiol 2004; 124: 719–727. 157. Gonzalez-Nunez D, Claria J, Rivera F et al. Increased levels of 12(S)-HETE 183. Nakagawa K, Holla VR, Wei Y et al. Salt-sensitive hypertension is in patients with essential hypertension. Hypertension 2001; 37: 334–338. associated with dysfunctional Cyp4a10 gene and kidney epithelial 158. Quintana LF, Guzman B, Collado S et al. A coding polymorphism in the sodium channel. J Clin Invest 2006; 116: 1696–1702. 12-lipoxygenase gene is associated to essential hypertension and 184. Capdevila JH, Falck JR. The CYP P450 arachidonic acid monooxygenases: urinary 12(S)-HETE. Kidney Int 2006; 69: 526–530. from to blood pressure regulation. Biochem Biophys Res 159. Chang WC, Su GW. Increase in 12-lipoxygenase activity in platelets of Commun 2001; 285: 571–576. spontaneously hypertensive rats. Biochem Biophys Res Commun 1985; 185. Omata K, Abraham NG, Escalante B et al. Age-related changes in renal 127: 642–648. cytochrome P-450 arachidonic acid metabolism in spontaneously 160. Sasaki M, Hori MT, Hino T et al. Elevated 12-lipoxygenase activity in the hypertensive rats. Am J Physiol 1992; 262: F8–F16. spontaneously hypertensive rat. Am J Hypertens 1997; 10: 371–378. 186. Omata K, Abraham NG, Schwartzman ML. Renal cytochrome P-450- 161. Stern N, Kisch ES, Knoll E. Platelet lipoxygenase in spontaneously arachidonic acid metabolism: localization and hormonal regulation in hypertensive rats. Hypertension 1996; 27: 1149–1152. SHR. Am J Physiol 1992; 262: F591–F599. 162. Nozawa K, Tuck ML, Golub M et al. Inhibition of lipoxygenase pathway 187. Escalante B, Sacerdoti D, Davidian MM et al. Chronic treatment with tin reduces blood pressure in renovascular hypertensive rats. Am J Physiol normalizes blood pressure in spontaneously hypertensive rats. 1990; 259: H1774–H1780. Hypertension 1991; 17: 776–779. 163. Munsiff AV, Chander PN, Levine S et al. The lipoxygenase inhibitor 188. Su P, Kaushal KM, Kroetz DL. Inhibition of renal arachidonic acid phenidone protects against proteinuria and stroke in stroke-prone omega-hydroxylase activity with ABT reduces blood pressure in the SHR. spontaneously hypertensive rats. Am J Hypertens 1992; 5: 56–63. Am J Physiol 1998; 275: R426–R438. 164. Natarajan R, Bai W, Lanting L et al. Effects of high glucose on vascular 189. Holla VR, Adas F, Imig JD et al. Alterations in the regulation of endothelial growth factor expression in vascular smooth muscle cells. androgen-sensitive Cyp 4a monooxygenases cause hypertension. Proc Am J Physiol 1997; 273: H2224–H2231. Natl Acad Sci USA 2001; 98: 5211–5216. 165. Natarajan R, Bai W, Rangarajan V et al. Platelet-derived growth factor BB 190. Gainer JV, Bellamine A, Dawson EP et al. Functional variant of CYP4A11 mediated regulation of 12-lipoxygenase in porcine aortic smooth 20-hydroxyeicosatetraenoic acid synthase is associated with essential muscle cells. J Cell Physiol 1996; 169: 391–400. hypertension. Circulation 2005; 111: 63–69. 166. Natarajan R, Rosdahl J, Gonzales N et al. Regulation of 12-lipoxygenase 191. Mayer B, Lieb W, Gotz A et al. Association of the T8590C polymorphism by cytokines in vascular smooth muscle cells. Hypertension 1997; 30: of CYP4A11 with hypertension in the MONICA Augsburg 873–879. echocardiographic substudy. Hypertension 2005; 46: 766–771. 167. Taylor AM, Hanchett R, Natarajan R et al. The effects of leukocyte-type 192. Makita K, Takahashi K, Karara A et al. Experimental and/or genetically 12/15-lipoxygenase on Id3-mediated vascular smooth muscle cell controlled alterations of the renal microsomal cytochrome P450 growth. Arterioscler Thromb Vasc Biol 2005; 25: 2069–2074. epoxygenase induce hypertension in rats fed a high salt diet. J Clin 168. Katoh T, Takahashi K, DeBoer DK et al. Renal hemodynamic actions of Invest 1994; 94: 2414–2420. lipoxins in rats: a comparative physiological study. Am J Physiol 1992; 193. Hannun YA. Functions of ceramide in coordinating cellular responses to 263: F436–F442. stress. Science 1996; 274: 1855–1859. 169. McGiff JC, Quilley J. 20-hydroxyeicosatetraenoic acid and 194. Zhang Y, Kolesnick R. Signaling through the sphingomyelin pathway. epoxyeicosatrienoic acids and blood pressure. Curr Opin Nephrol Endocrinology 1995; 136: 4157–4160. Hypertens 2001; 10: 231–237. 195. Pena LA, Fuks Z, Kolesnick R. Stress-induced apoptosis and the 170. Roman RJ. P-450 metabolites of arachidonic acid in the control of sphingomyelin pathway. Biochem Pharmacol 1997; 53: 615–621. cardiovascular function. Physiol Rev 2002; 82: 131–185. 196. Ueda N, Camargo SM, Hong X et al. Role of ceramide synthase in oxidant 171. Capdevila JH, Falck JR. Biochemical and molecular properties of the injury to renal tubular epithelial cells. J Am Soc Nephrol 2001; 12: cytochrome P450 arachidonic acid monooxygenases. Prostaglandins 2384–2391. Other Lipid Mediat 2002; 68–69: 325–344. 197. Ueda N, Kaushal GP, Hong X et al. Role of enhanced ceramide 172. Zhao X, Imig JD. Kidney CYP450 enzymes: biological actions beyond generation in DNA damage and cell death in chemical hypoxic injury to drug metabolism. Curr Drug Metab 2003; 4: 73–84. LLC-PK1 cells. Kidney Int 1998; 54: 399–406. 173. Roman RJ, Maier KG, Sun CW et al. Renal and cardiovascular actions of 198. Zager RA, Conrad S, Lochhead K et al. Altered sphingomyelinase and 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids. Clin Exp ceramide expression in the setting of ischemic and nephrotoxic acute Pharmacol Physiol 2000; 27: 855–865. renal failure. Kidney Int 1998; 53: 573–582. 174. Harder DR, Gebremedhin D, Narayanan J et al. Formation and action of a 199. Zager RA, Iwata M, Conrad DS et al. Altered ceramide and sphingosine P-450 4A metabolite of arachidonic acid in cat cerebral microvessels. Am expression during the induction phase of ischemic acute renal failure. J Physiol 1994; 266: H2098–H2107. Kidney Int 1997; 52: 60–70. 175. Imig JD, Zou AP, Stec DE et al. Formation and actions of 20- 200. Kalhorn T, Zager RA. Renal cortical ceramide patterns during ischemic hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol 1996; and toxic injury: assessments by HPLC-mass spectrometry. Am J Physiol 270: R217–R227. 1999; 277: F723–F733. 176. Oyekan AO, McAward K, Conetta J et al. Endothelin-1 and CYP450 201. Zager RA, Conrad DS, Burkhart K. Ceramide accumulation during arachidonate metabolites interact to promote tissue injury in DOCA-salt oxidant renal tubular injury: mechanisms and potential consequences. hypertension. Am J Physiol 1999; 276: R766–R775. J Am Soc Nephrol 1998; 9: 1670–1680. 177. Oyekan AO, Youseff T, Fulton D et al. Renal cytochrome P450 202. Itoh Y, Yano T, Sendo T et al. Involvement of de novo ceramide synthesis omega-hydroxylase and epoxygenase activity are differentially in radiocontrast-induced renal tubular cell injury. Kidney Int 2006; 69: modified by nitric oxide and sodium chloride. J Clin Invest 1999; 104: 288–297. 1131–1137. 203. Basnakian AG, Ueda N, Hong X et al. Ceramide synthase is essential for 178. Imig JD, Deichmann PC. Afferent arteriolar responses to ANG II involve endonuclease-mediated death of renal tubular epithelial cells induced activation of PLA2 and modulation by lipoxygenase and P-450 by hypoxia-reoxygenation. Am J Physiol Renal Physiol 2005; 288: pathways. Am J Physiol 1997; 273: F274–F282. F308–F314. 179. Zou AP, Fleming JT, Falck JR et al. 20-HETE is an endogenous inhibitor of 204. Yi F, Zhang AY, Janscha JL et al. Homocysteine activates NADH/NADPH the large-conductance Ca(2+)-activated K+ channel in renal arterioles. oxidase through ceramide-stimulated Rac GTPase activity in rat Am J Physiol 1996; 270: R228–R237. mesangial cells. Kidney Int 2004; 66: 1977–1987.

Kidney International (2007) 71, 1105–1115 1115