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Roles of Lipid Mediators in Kidney Injury

Chuan-Ming Hao, MD, and Matthew D. Breyer, MD

Summary: Small lipids such as eicosanoids exert diverse and complex functions. In additionto their role in regulating normal kidney function, these lipids also play important roles in thepathogenesis of kidney diseases. Increased glomerular cyclooxygenase (COX)1 or COX2expression has been reported in patients with nephritis and in animal models of nephritis.COX inhibitors have shown beneficial effects on lupus nephritis and passive Heymannnephritis, but not anti-Thy1.1–induced nephritis. 5-Lipoxygenase–derived leukotrienes areinvolved in inflammatory glomerular injury. Lipoxygenase product 12-hydroxyeicosatetra-enoic acid may mediate angiotensin II and transforming growth factor �-induced mesangialcell abnormality in diabetic nephropathy. P450 arachidonic acid mono-oxygenase–derived20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids are involved in several formsof kidney injury, including renal injury in metabolic syndrome. Ceramide also has been shownto be an important signaling molecule that is involved in the pathogenesis of acute kidneyinjury caused by ischemia/reperfusion and toxic insults. Those pathways should providefruitful targets for intervention in the pharmacologic treatment of renal disease.Semin Nephrol 27:338-351 © 2007 Elsevier Inc. All rights reserved.Keywords: Cyclooxygenase, lipoxygenase, P450 monooxygenase, diabetic nephropathy,nephritis, prostaglandin

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n extensive body of evidence shows thatsmall lipids participate as mediators in avariety of transmembrane signaling cas-

ades, mediating multiple cellular processesuch as cell differentiation, proliferation, andpoptosis.1-4 These lipids include eicosanoids,atty acids, glycerophospholipids, and cer-mide.1-4 In addition to their roles in regulatinghysiologic function, these lipid mediators alsoave been shown to play important roles in theathophysiology of inflammation, asthma, can-er, diabetes, and hypertension,1-5 pointing tootential therapeutic targets at above-men-ioned lipid mediators or the enzyme responsi-le for their biosynthesis or the receptor medi-ting their actions. The present review focusesn the current understanding of the roles ofrachidonic acid–derived lipid mediators in tis-ue injury and the repair process in diseasedidney.

ivision of Nephrology, Department of Medicine, Vanderbilt University, andVeterans Affairs Medical Center, Nashville, TN.

ddress reprint requests to Chuan-Ming Hao, S3223 MCN, Division ofNephrology, Vanderbilt University Medical Center, Nashville, TN37232. E-mail: [email protected]

270-9295/07/$ - see front matter

d2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2007.02.008

Semina38

RACHIDONIC ACIDND PHOSPHOLIPASE A2

rachidonic acid is a precursor of an array ofioactive lipids, including prostanoids, leukotri-nes, and hydroxyeicosatetraenoic acids (HETEs)nd epoxyeicosatrienoic acids (EETs), producedhrough cyclooxygenase (COX), lipoxygenaseLO), and cytochrome P450 monooxygenaseCYP450) pathways, respectively.2,3,5-7 Collec-ively, these arachidonic acid–derived lipids arealled eicosanoids (eicosa, Greek for 20, refer-ing to 20 carbon fatty acids).

Cellular levels of free arachidonic acid avail-ble for eicosanoid production are controlledrimarily by phospholipase A2 (PLA2).8 Thus

ar, more than 20 PLA2s have been identified,hich have been classified into 4 groups: secre-

ory PLA2 (sPLA2), cytosolic PLA2 (cPLA2), cal-ium-independent PLA2, and platelet-activatingactor (PAF) acetylhydrolases.8,9 Six membersf the cPLA2 family have been identified:PLA2�, �, �, �, �, and �.10 Among them,PLA2� (IVA PLA2) is best characterized and isuggested to be a key player regulating arachi-

onic acid release for eicosanoid biosynthe-

rs in Nephrology, Vol 27, No 3, May 2007, pp 338-351

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Lipid mediators in kidney injury 339

is.8,9 The activity of cPLA2 is regulated by mi-ogen-activated protein kinase, protein kinase, and Ca��-calmodulin–dependent kinase.11-13

ndothelin, angiotensin II, and vasopressinave been reported to activate cPLA2.14-20

In the kidney, studies show that PLA2 activ-ty can be induced by a variety of stimuli, in-luding oxidative stress, complement C5b-9,ypoxia, and mechanical stretch.21-24 cPLA2 haseen shown to enhance H2O2-induced cytotox-

city in kidney epithelial cells and mesangialells.25,26 cPLA2 and its products have beenhown to participate in several pathogenic pro-esses, including diabetic nephropathy, anti-hy1 glomerulonephritis, and ischemic kidney

njury.8,10 Recently, considerable evidence hasuggested that secretary PLA2s, particularlyPLA2 IIa, sPLA2 V, and sPLA2 X, are involvedn atherosclerotic lesions.27-29 The role of thesePLA2s in the kidney remain to be defined.

OX-DERIVED PROSTANOIDS

rachidonic acid can be metabolized to prosta-oids via the COX pathway. COX first convertsree arachidonic acid to prostaglandin (PG)G2ia its bis-oxygenase activity, and the unstableGG2 then is converted to PGH2 by the perox-

dase activity of COX.30 PGH2 subsequently isetabolized to more stable biologically activerostanoids including PGE2, prostacyclin (PGI2),GF2�, PGD2, and thromboxane A2 (TxA2) byistinct synthases. Each prostanoid acts on spe-ific and distinct cell surface G-protein–coupledeceptor(s)31,32 or on nuclear receptors such aseroxisome proliferator-activated receptor �nd peroxisome proliferator-activated receptor(Fig. 1).33-36

Prostanoids rapidly are degraded metaboli-ally, limiting their effect to the immediate vi-inity of their synthetic site, accounting forheir autocrine or paracrine function. The bio-ogic effects of COX-derived prostanoids areiverse and complex, depending on which pro-tanoid is produced and which receptor is avail-ble.31,32 Thus, the effects of prostanoids onidney function rely on distinct enzymatic ma-hinery that couples phospholipase and COX topecific prostanoid synthase in specific cells,

ielding a specific prostanoid that acts, through d

utocrine or paracrine, on a specific G-protein–oupled receptor, exerting its distinct effect.31

yclooxygenases

wo isoforms of COX have been identified,esignated COX1 and COX2.37-40 COX1 appearso serve a constitutive housekeeping role, beingesponsible for maintaining basic physiologicunction such as cytoprotection of the gastricucosa and control of platelet aggrega-

ion.6,30,41 Conversely, COX2 is induced by in-ammatory mediators and mitogens, and ishought to play an important role in pathophys-ologic processes including angiogenesis, in-ammation, and tumorigenesis.6,7,30,41 How-ver, recent studies have indicated that COX2lso serves housekeeping functions. Gene-tar-eting experiments have shown a critical rolef COX2 in kidney development, ovulation, andarturition.42-45 Clinical and animal studies alsoave shown an important role of COX2 in main-aining cardiovascular homeostasis.46-48 The ex-ression of these 2 isoforms of COX in theidney has been documented. COX1 is highlyxpressed in the collecting duct, and a lowevel of COX1 also is detected in interstitialells.49-51 In contrast, COX2 is expressed pre-

igure 1. Cyclooxygenase pathway of arachidonic acidetabolism.

ominantly in renal medullary interstitial cells,

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340 C.-M. Hao and M.D. Breyer

n the cortical thick ascending limb, and in cellsssociated with macula densa under normalonditions.38,49,52

rostanoid Synthases

OX-mediated arachidonate metabolite inter-ediate PGH2 is catalyzed further by prosta-

oid synthase. Prostanoid synthases includeGE2 synthase (PGES), prostacyclin synthasePGIS), PGD synthase (PGDS), PGF synthase, andhromboxane synthase, responsible for PGE2,GI2, PGD2, PGF2�, and TxA2 biosynthesis, re-pectively.41,53 At least 3 PGE synthases have beendentified: microsomal PGE synthase 1 (mPGES1),

icrosomal PGE synthase (mPGES2), and cytoso-ic PGE synthase.54-56 mPGES1 displays a high cat-lytic activity relative to other PGESs.54,57 Thexpression of mPGES1 is induced by cytokinesnd inflammatory stimuli.54 In contrast, the ex-ression of cytosolic PGES and mPGES2 is not

nducible.56,58 PGD2 is synthesized from PGH2,atalyzed by PGDS.59 Two distinct types ofGDS have been identified: the lipocalin-typeGDS and the hematopoietic PGDS.59,60 PGF2�an be synthesized from PGH2 by 9,11 endo-eroxide reductase.61 PGF2� also can be syn-hesized from PGE2 by PGE 9-ketoreduc-ase.62,63

Molecular and/or pharmacologic studiesave shown PGES expression or PGE2 biosyn-hesis in most cell types or tissues involved inmmunologic and inflammatory reaction, in-luding the thymus, spleen, dendritic cells,acrophages, eosinophils, neutrophils, andast cells.64 PGDS and TxAS expression or ac-

ivity also has been described in dendritic cells,icrophages, eosinophils, neutrophils, andast cells.64 In macrophages, PGE2 and TxA2

re major prostanoids, whereas mast cells pre-ominantly generate PGD2.64 Resting macro-hages produce TxA2 in excess of PGE2, thisatio changes to favor PGE2 biosynthesis afternflammatory agent lipopolysaccharide treat-

ent.64 These studies are consistent with im-ortant roles of prostanoids in the regulation of

mmunologic and inflammatory reactions.The distribution of prostanoid synthases

ithin the kidney is less well characterized. Inhe kidney, mPGES1 is expressed in collecting

uct and medullary interstitial cells.65,66 Al- i

hough mPGES1 has been reported to be func-ionally coupled to COX2,58 in renal collectinguct mPGES1 appears to be coupled mainly toOX1.65 Low levels of mPGES2 and cytosolicGES also are detected in the kidney.67,68

hromboxane synthase is detected mainly inhe glomeruli.66 PGI synthase appears to beocalized mainly to vasculature in the kidney.66

everse-transcription polymerase chain reac-ion showed that lipocalin-type PGDS is ex-ressed strongly in kidney cortex and outeredulla; although hematopoietic PGDS mes-

enger RNA (mRNA) is detected only in micro-issected outer medullary collecting duct.66

GE2 is the most abundant prostanoid in theidney, followed by PGI2, PGF2�, and TxA2.69

nder basal conditions, both COX1 and COX2athways are responsible for the biosynthesisf these prostanoids.69 In contrast, the COX2athway contributes to angiotensin II–inducedGE2 and PGI2 generation in the kidney.69 Theellular sites where these prostanoids are syn-hesized remain to be defined.

rostanoid Receptors

diverse family of membrane-spanning G-pro-ein–coupled prostanoid receptors has beenloned and characterized. These include the-prostanoid (DP), E-prostanoid (EP), F-prosta-oid (FP), I-prostanoid (IP), and T-prostanoidTP) receptors, each of which selectively reactsith PGD2, PGE2, PGF2�, PGI2, or TXA2, re-

pectively.31,32 Four subtypes of EP receptorsave been identified: EP1, EP2, EP3, andP4.31,32 Each prostanoid receptor activates aistinct G-protein–coupled signaling pathway.he IP, DP, EP2, and EP4 receptors are coupled

o the stimulatory G protein that signals byncreasing intracellular cyclic adenosine mono-hosphate level, whereas the TP, FP, and EP1eceptors induce calcium mobilization.31,32 TheP3 receptor is coupled to an inhibitory G pro-ein and reduces cyclic adenosine monophos-hate synthesis.31,32

The regulation of prostanoid receptors pro-ides additional mechanisms by which COX-erived prostanoids exert diverse actions inhysiologic and pathophysiologic processes.ll 4 EP receptors have been described in major

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ymphocytes, macrophages, and mast cells.64 Itas been proposed that activation of differenteceptors on different cells at different stages ofnflammation may account for the proinflamma-ory or anti-inflammatory action of PGE2.64,70

The intrarenal localization of these prostanoideceptors and the consequences of their activa-ion have been characterized only partially.71 EP1nd EP3 mRNA expression predominates in theollecting duct and thick limb, respectively,here their stimulation reduces NaCl and water

bsorption, promoting natriuresis and diure-is.71 The FP receptor is highly expressed in theistal convoluted tubule and collecting duct,here it may exert distinct effects on renal salt

ransport.72 Although only low levels of EP2-eceptor mRNA are detected in the kidney andts precise intrarenal localization is uncertain,

ice with targeted disruption of the EP2 recep-or show salt-sensitive hypertension, suggestinghat this receptor may play an important role inalt excretion.73,74 In contrast, EP4-receptorRNA is expressed predominantly in the glo-erulus, where it may contribute to the regu-

ation of glomerular hemodynamics and reninelease.31,75 The IP-receptor mRNA is highly ex-ressed in the afferent arteriole, where it alsoay dilate renal arterioles and stimulate renin

elease.31 Conversely, TP receptors in the glo-erulus may counteract the effects of these

ilator prostanoids and increase glomerular re-istance. At present, there is little evidence forP-receptor expression in the kidney.31

ole of COX-Derivedrostanoids in Inflammatory Renal Injury

he role of COX-derived prostanoids in immuno-ogic and inflammatory disease has been well doc-mented.30,41 COX2 expression and prostanoidiosynthesis can be induced in macrophage, den-ritic cells by such inflammatory agents as lipo-olysaccharide, interleukin-1�, and interferon.30,58,76 Prostanoids, particularly PGE2 and PGI2,ave been shown to enhance inflammatory reac-ions,30,64 and on the other hand prostanoids alsoave been shown to have anti-inflammatory ef-ects.70,77 The proinflammatory or anti-inflamma-ory effects of prostanoids is dependent on thepecific prostanoid-receptor subtype, cell popula-

ion, and context of activation.70,77 h

Increased glomerular COX1 or COX2 expres-ion has been reported in patients with nephritisnd in animal models of nephritis.78-81 Glomerularxpression of COX2 is up-regulated in patientsith active lupus nephritis and in the lupus ne-hritis animal model.78,82 In the murine lupusephritis model, combined treatment with myco-henolate mofetil and COX2 inhibitor signifi-antly improved survival and reduced renal dam-ge compared with mycophenolate mofetil alone,upporting a role of COX-derived products in theathogenesis of renal damage in lupus nephritis.82

OX2 inhibition also has shown a beneficial ef-ect on passive Heymann nephritis, a model ofembranous nephropathy.83,84 Cell culture stud-

es show that thromboxane A2 can be a mediatorf complement-induced cytotoxicity of glomeru-

ar epithelial cells.83 In contrast, in an anti-Thy1.1lomerulonephritis model, an animal model ofesangioproliferative glomerulonephritis that is

haracterized by endothelial injury, COX2 inhibi-ion is associated with increased mesangiolysis,lbuminuria, and delayed recovery from glomer-lar injury.85 Further studies have suggested thatealing of injured glomerular capillary endothe-

ium in this model may depend on COX2-derivedrostanoids; COX2 inhibition may lead to im-aired capillary endothelium healing.85 Furthertudies are required to define the precise roles ofrostanoids in different forms of glomerulone-hritis.

enal COX-Derivedrostanoids and Diabetic Nephropathy

iabetic nephropathy is characterized by mi-roalbuminuria, glomerular hypertrophy, mesan-ial expansion with glomerular basement mem-rane thickening, arteriolar hyalinosis, and globallomerular sclerosis, which ultimately leads torogression to proteinuria and renal failure.86,87

ncreased glomerular filtration rate (hyperfiltra-ion) typifies the early stages of diabetic nephrop-thy.86,87 Animal studies show that in streptozoto-in (STZ)-induced type I diabetic rats, renal PGE2,GI2, and TxB2 increase.88,89 COX2 expressionlso is increased in the thick ascending limb andacula densa in both type I STZ diabetic and type

I diabetic Zucker rats.90-93 Enhanced maculaensa COX2 expression also has been reported in

uman diabetic kidneys.94 Selective COX2 inhibi-

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ion significantly reduces glomerular hyperfiltra-ion in STZ-induced diabetic rats, consistent withhe role of COX2-derived prostanoids in increasedenal blood flow in the diabetic kidney.90 Thedentity of these prostanoids and their cognateeceptors involved in the pathogenesis of diabeticephropathy has not been characterized com-letely. Available data have shown that EP1- andP3-receptor mRNA expression increases in theidney of STZ-induced and genetic (Akita) type Iiabetic mice.95 EP1-receptor antagonist treat-ent ameliorates renal and glomerular hypertro-hy, and decreases mesangial expansion.96

hromboxane receptor (TP) antagonist also haseen reported to attenuate proteinuria and ame-

iorated histologic changes of diabetic nephropa-hy in diabetic apolipoprotein E–deficient mice.97

he role of COX-derived prostanoids in the patho-enesis of diabetic nephropathy remains to bexplored further.

enal COX-Derived Prostanoidsnd Glomerulosclerosisn Chronic Kidney Disease

everal studies have suggested that COX-de-ived prostanoids also may modify renal func-ion and glomerular damage in chronic renalailure.98-101 After subtotal renal ablation, renal

igure 2. Lypoxygenase pathway of arachidonic acid met

ortical COX2 expression is increased.100,101 n

his increased COX2 expression is most promi-ent in the macula densa and surrounding corticalhick ascending limb (cTAL).100,101 IncreasedOX2 immunoreactivity in glomerular mesangialells and podocytes from remnant kidneys alsoas been reported.100,101 Selective COX2 inhibi-ion decreases proteinuria and inhibits the de-elopment of glomerular sclerosis.100,101 Thesetudies are consistent with a role of COX2-erived prostanoids in the pathogenesis oftructural and functional deterioration of theidney in chronic kidney disease.

IPOXYGENASE-DERIVEDICOSANOIDS: 5-, 12-, AND5-HETES AND LEUKOTRIENES

rachidonic acid also can be oxidized by li-oxygenases to form HETEs and leukotrienesFig. 2).102,103 LOs are a family of nonhemeron-containing enzymes that insert molecularxygen into polyunsaturated fatty acids such asrachidonic acid and linoleic acid.102 At least 6unctional human lipoxygenases have beenloned: 5-lipoxygenase (gene name: ALOX5),latelet-type 12-lipoxygenase (gene name:LOX12), 12/15-lipoxygenase (leukocyte-type2-LO for mice, 15-LO type 1 for human, gene

. ➀ Leukotriene A4 hydrolase; ➁ leukotriene C4 synthase.

ame: ALOX15), epidermal-type 12-lipoxygen-

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se (gene name: ALOXE3), 12(R)-lipoxygenasegene name: ALOX12B), and 15-lipoxygenaseype 2 (8-lipoxygenase in mice, gene name:LOX15B).103

5-lipoxygenase is the key enzyme in leukotri-ne biosynthesis.103 5-lipoxygenase catalyzeshe generation of leukotriene A4 (LTA4) in theresence of 5-LO–activating protein (FLAP).TA4, in turn, is converted by LTA4 hydrolaseo LTB4, capable of activating LTB4 receptors.TA4 also can be converted to cysteinyl leuko-rienes (LTC4, LTD4, and LTE4) through leuko-riene C4 synthase.102 LTC4 and LTD4 contractascular smooth muscle cells and increase vas-ular permeability.104-106 LTB4 is a potent che-otactic substance and increases polymorpho-

uclear leukocytes (PMN) aggregation anddhesion to the endothelium.106 These leukotri-nes usually are released locally, primarily by leu-ocytes. These properties of leukotrienes are con-istent with their role in mediating inflammatorynd allergic reactions.107-110 Mice with 5-LO geneisruption show a reduced inflammatory reac-ion, supporting the proinflammatory action of-LO–derived metabolites.103,111

12-LO catalyzes the formation of oxidized lip-ds (12[S]-HETE). Human 15-LO type 1 sharesigh homolog with rodent leukocyte-type 12-LO;oth can mediate the formation of 12(S)-HETEnd 15(S)-HETE from arachidonic acid, and thusre classified as 12/15-LO.102,103,112 The produc-ion of 12(s)-HETE and 15(s)-HETE has been de-ected in vascular smooth muscle cells, endothe-ial cells, monocytes, and platelets.113-116

ubstantial evidence suggests that these eico-anoids play an important role in systemicomeostasis and renal-cardiovascular pathol-gy.113-116 Recent studies have indicated that2/15-lipoxygenase products also are involved

n the pathogenesis of atherosclerosis. 12/15-ipoxygenase gene deletion is associated witheduced atherosclerosis in animal models.117-120

ole of Lipoxygenase-Derivedroducts in Glomerular Injury

-LO–derived products have been documentedo play an important role in mediating glomer-lar immune injury.121,122 5-LO mRNA and-LOX-activating protein (FLAP) mRNA are de-

ected in the glomeruli and vasa recta.123 Both t

eukotriene-receptor B4 and the cysteinyl leu-otriene–receptor type 1 are expressed selec-ively in the glomerulus.123 These studies sug-est that 5-LO products are involved in theegulation of glomerular function. Glomerularynthesis of LTB4 and LTC4/LTD4 is enhancedarkedly in the early course of several forms of

lomerular immune injury, including nephro-oxic serum nephritis, anti-Thy1 nephritis, cat-onic bovine gamma globulin–induced glomer-lar injury, and passive Heymann nephritis.121

TD4 plays an important role in the reductionf the glomerular filtration rate in the acutehase of the injury by virtue of its potent vaso-onstrictor action and contraction of mesangialells.121,124 LTD4 also has been reported to in-rease intraglomerular pressure, which may bessociated with proteinuria.125 A FLAP antago-ist has been shown to reduce proteinuria inatients with glomerulonephritis, supporting aole of leukotrienes in proteinuria.121 LTB4, aotent promoter of PMN attraction, partici-ates in glomerular damage by amplifying PMN-ependent mechanisms of injury.124

ole of LO-Derived Metabolites in theathogenesis of Diabetic Nephropathy

ccumulating evidence indicates that LO-derivedroducts contribute to the pathogenesis of dia-etic complications including diabetic nephropa-hies.112 12/15-LO is detected in renal microves-els, glomeruli, and mesangial cells.126-128 12/5-LO levels are increased in the glomeruli ofxperimental diabetic animals.128-130 High glu-ose levels have been shown to directly in-rease 12/15-LO expression in cultured mesan-ial cells.129 The 12/15 LO pathway has beenhown to be a critical mediator of transformingrowth factor �� and angiotensin II–inducedesangial cell hypertrophy and extracellularatrix accumulation.131-133 Angiotensin II and

ransforming growth factor � treatment signifi-antly increased 12-LO mRNA expression andormation of the 12-LO product 12(S)-HETE inultured rat mesangial cells.112 Angiotensin II–nduced mesangial cell hypertrophy and extra-ellular matrix synthesis in cultured rat mesan-ial cells can be blocked by an LO inhibitor or

argeted 12/15 LO gene deletion.112,131-133

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YP450 MONOOXYGENASE–DERIVEDICOSANOIDS: 20-HETE AND EETS

ree arachidonic acid also can be oxidized byhe cytochrome P450 monooxygenase (CYP50) to produce hydroxy- and epoxy-arachi-onic acid derivatives.5,134,135 The majorYP450-catalyzed reactions in most tissues areediated by epoxygenase and �-hydroxylase

ctivities of the CYP450 family, which are re-ponsible for biosynthesis of EETs and 20-HETE,espectively (Fig. 3).5,134,135 Molecular biologytudies have identified members of the P450YP2C and CYP4A gene subfamilies as func-

ionally relevant epoxygenases and �-hydroxy-ases, respectively.134-137 20-HETE is a potentasoconstrictor.135,138-142 EETs are produced inhe vascular endothelium, and are potent vaso-ilators.122,134,135,143,144 EETs also are produced

n tubules including the proximal tubule andollecting ducts in the rodent kidney.144,145 EETas been shown to inhibit the amiloride-sensi-ive epithelial sodium channel (ENaC) activi-y,146 which may contribute to their natriureticffect. EETs also have been shown to mediatehe natriuretic effect of angiotensin II.134,147

enal CYP450-Derived Arachidonateetabolites in Metabolic Syndrome

he metabolic syndrome is a constellation ofhysical and laboratory abnormalities includingypertension, hyperglycemia, hyperlipidemia,nd abdominal obesity.148 Recent studies indi-ate that the metabolic syndrome is not onlyn important risk factor for cardiovascular dis-

Figure 3. CYP450 monooxygenase

ase, but also is associated with chronic kid- o

ey disease.149-151 The mechanism underlyinghis association has not been elucidated com-letely.152 Recent studies have shown that inenetic (Zucker rats) and high-fat diet–inducedbese animals, renal levels of CYP450-derivedicosanoids are reduced,92,153 accompanied byeduced CYP2C11 and CYP2C23 protein ex-ression in renal vessels of obese Zucker rats.92

educed CYP450-derived product appears toe associated with renal vascular dysfunction inbese animals. NO-dependent acetylcholine-

nduced vasodilatation is reduced in obese kid-eys.154 This renal vascular dysfunction inbese rats can be reversed by fenofibrate, aeroxisome proliferator-activated receptor �gonist that increases CYP2C11 and CYP2C23xpression.154 A high-fat diet that reduces renalET synthesis also reduces renal sodium excre-ion, suggesting a potential association betweeneduced EET production and sodium retention,hich may lead to hypertension.155

ole of CYP450-Derived Arachidonateetabolites in Renal Damage

everal studies have shown the role of arachid-nate epoxygenase–derived metabolites in re-in-angiotensin II–induced kidney damage.ransgenic rats overexpressing human reninnd angiotensinogen genes display marked hy-ertension, and end-organ damage including re-al failure and proteinuria.156,157 The kidneys ofhese rats show increased infiltration of inflam-atory cells and activation of nuclear factor � B

nd activating protein-1 (AP1).158 Renal arachid-

ay of arachidonic acid metabolism.

nate epoxygenase activity and protein levels

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f CYP2C11, CYP2C23, and CYP2J are reducedignificantly in this animal model.158-160 Impor-antly, treatment with fenofibrate increases ep-xygenase expression, normalizes blood pres-ure and albuminuria, reduces nuclear factor �

activity, and renal leukocyte infiltration inhese rats, suggesting that hypertension andenal damage in this rat model is associatedith down-regulation of P450 epoxygenase-de-endent arachidonic acid metabolism.158-160

Increased EET formation has been reportedn the kidney of rats with liver cirrhosis.161

lthough it is well documented that renal vaso-onstriction leading to impaired renal functionccurs during cirrhosis, this result suggests that

ncreased EET synthesis may be a homeostaticesponse to preserve renal perfusion.161 Re-uced CYP arachidonate hydroxylase activitynd 20-HETE levels have been reported in theidney after ischemia and reperfusion.162 Re-uced CYP4A protein expression and enzymectivity in ischemia/reperfusion is suggested toe an adaptive mechanism to preserve renalasculature from excessive vasoconstriction.162

Recent studies have suggested that CYP hy-roxylase–derived product 20-HETE plays an im-ortant role in the maintenance of the glomerularrotein permeability barrier.163 An in vitro glo-erular albumin permeability study using isolated

at glomeruli shows that puromycin amino-ucleoside significantly increases glomerular albu-in permeability.163 20-HETE treatment blocksuromycin aminonucleoside–induced increase inlbumin permeability.163 Clofibrate that increasesYP4A expression also prevented the isolatedlomeruli from puromycin aminonucleoside–in-uced increases in albumin permeability.163 Thisesult is consistent with earlier studies showingompounds that reduce proteinuria, such as an-iotensin-converting enzyme inhibitor and cy-losporine A, also increase 20-HETE biosyn-hesis,164-166 suggesting a potential protective rolef CYP hydroxylase–derived products in main-aining glomerular permeability barrier function.

OLE OF SPHINGOMYELINND CERAMIDE IN THEORMAL AND DISEASED KIDNEY

eramide is also an important signaling mole-

ule, playing an important role in cellular re- m

ponses to stress, cell growth and differentia-ion, and apoptosis.167-169 Ceramide is producedainly from the hydrolysis of sphingomyelin,

atalyzed by sphingomyelinase (Fig. 4).167,168

eramide also can be generated throughondensation of sphingosine or sphinganinend fatty acyl—coenzyme (Co)A by ceramideynthase (Fig. 4).169 The direct targets of cer-mide include ceramide-activated protein phos-hatase, ceramide-activated protein kinase, androtein kinase C�. Ceramide-activated proteinhosphatase is related to the PPA2 family ofhosphatases, and can be inhibited by okadaiccid.167 A number of intracellular signaling mol-cules have been shown to be responsive toellular ceramide levels, including Raf-1, mito-en-activated protein kinase, arachidonic acid,-myc, the retinoblastoma gene products, andnhibitory �B (I�B).168 Ceramide synthesis cane induced by 1,25(OH)2 VitD3, tumor necro-is factor �, endotoxin, interferon �, interleu-in-1, retinoic acid, progesterone, and ionizingrradiation.167 Numerous stresses that initiatepoptosis have been associated with rapid cer-mide generation, including ionizing radiation,eat shock, oxidative stress, daunorubicin, andincristine, consistent with the critical role oferamide in apoptosis.169

It has been documented that ceramide isnvolved in the pathogenesis of acute kidneynjury caused by ischemia/reperfusion, toxic in-ults, and oxidative stress.170-173 In normal

igure 4. Ceramide biosynthesis.

ouse kidney cortex, C24, C22, and C16 cer-

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mides have been identified.174 Ischemia/reper-usion or nephrotoxic injury (glycerol-mediatedyohemoglobinuria, radiocontrast) cause a

ransient reduction of renal ceramide levels,ollowed by a 2- to 3-fold increase in ceramideevels.173,175,176 The increased ceramide level af-er renal injury does not seem to be associatedith enhanced hydrolysis of sphingomyelin be-

ause sphingomyelinase expression is not in-reased but rather is reduced throughout thexperiments.172 In contrast, hypoxia-reoxygen-tion or radiocontrast-induced renal tubular ep-thelial cell injury is attenuated by the ceramideynthase inhibitor, fumonisin B1, suggestinghat increased ceramide synthase activity is re-ponsible for increased ceramide generation,eading to apoptotic change of the renal epithe-ial cells.176,177 Of interest, recent studies in mes-ngial cells show that ceramide mediates en-anced collagen synthesis in response toomocysteine, which has been documented tolay an important role in glomerular sclerosis.178

UMMARY

icosanoids exert diverse and complex func-ions. The specific effect of each eicosanoidepends on sequential enzymatic machinery inspecific cell, yielding a specific eicosanoid,

xerting its distinct function. The biosynthesisf each eicosanoid is regulated at multiple lev-ls from phospholipase A2, which catalyzes theelease of arachidonic acid to specific enzymeshat catalyze the formation of bioactive eico-anoids. Arachidonate-derived eicosanoids in-luding prostanoids, leukotrienes, 12/15-ETEs, EETs, and HETEs, and sphingomyelin-erived ceramide, play important roles inaintaining normal renal function. They also

re involved in the pathophysiology of diabeticephropathy, and inflammatory or toxic glo-erular injury. Those signaling pathways

hould provide fruitful targets for interventionn the pharmacologic treatment of renal dis-ase.

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Roles of Lipid Mediators in Kidney InjuryARACHIDONIC ACID AND PHOSPHOLIPASE A2COX-DERIVED PROSTANOIDSCyclooxygenasesProstanoid SynthasesProstanoid ReceptorsRole of COX-Derived Prostanoids in Inflammatory Renal InjuryRenal COX-Derived Prostanoids and Diabetic NephropathyRenal COX-Derived Prostanoids and Glomerulosclerosis in Chronic Kidney Disease

LIPOXYGENASE-DERIVED EICOSANOIDS: 5-, 12-, AND 15-HETES AND LEUKOTRIENESRole of Lipoxygenase-Derived Products in Glomerular InjuryRole of LO-Derived Metabolites in the Pathogenesis of Diabetic Nephropathy

CYP450 MONOOXYGENASE–DERIVED EICOSANOIDS: 20-HETE AND EETSRenal CYP450-Derived Arachidonate Metabolites in Metabolic SyndromeRole of CYP450-Derived Arachidonate Metabolites in Renal Damage

ROLE OF SPHINGOMYELIN AND CERAMIDE IN THE NORMAL AND DISEASED KIDNEYSUMMARYREFERENCES

roles of lipid mediators in kidney...

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