Renal arterial 20-hydroxyeicosatetraenoic acid levels:regulation by cyclooxygena



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发表于 2009-4-21 13:50 |显示全部帖子

作者：Monica K.Cheng, John C.McGiff,  Mairead A.Carroll作者单位：Department of Pharmacology, New York Medical College,Valhalla, New York

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      【摘要】
   20-HETE, a potent vasoconstrictor, isgenerated by cytochrome P -450 -hydroxylases and is theprincipal eicosanoid produced by preglomerular microvessels. It isreleased from preglomerular microvessels by ANG II and is subject tometabolism by cyclooxygenase (COX). Because low-salt (LS) intakestimulates the renin-angiotensin system and induces renal corticalCOX-2 expression, we examined 20-HETE release from renal arteries(interlobar and arcuate and interlobular arteries) obtained from 6- to7-wk-old male Sprague-Dawley rats fed either normal salt (0.4% NaCl)or LS (0.05% NaCl) diets for 10 days. With normal salt intake, thelevels of 20-HETE recovered were similar in arcuate and interlobulararteries and interlobar arteries: 30.1 ± 8.5 vs. 24.6 ± 5.3 ng · mgprotein 1 · 30 min 1,respectively. An LS diet increased 20-HETE levels in the incubate ofeither arcuate and interlobular or interlobar renal arteries only whenCOX was inhibited. Addition of indomethacin (10 µM) to the incubateof arteries obtained from rats fed an LS diet resulted in a two- tothreefold increase in 20-HETE release from arcuate and interlobulararteries, from 39.1 ± 13.2 to 101.8 ± 42.6 ng · mgprotein 1 · 30 min 1 ( P ± 29.4 ng · mgprotein 1 · 30 min 1 ( P inhibited. An LS diet enhanced vascular expression ofcytochrome P -4504A and COX-2 in arcuate and interlobulararteries; COX-1 was unaffected. Metabolism of 20-HETE by COX isproposed to represent an important regulatory mechanism in settingpreglomerular microvascular tone.   y  j) O8 J5 X& y
      【关键词】 renal microvessels salt depletion eicosanoids cytochrome P
   INTRODUCTION
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PREGLOMERULAR SMALL ARTERIES and arterioles (PGA) occupy a key position in theregulation of renal circulation ( 19 ) and are endowed withhigh levels of cytochrome P -450 (CYP) / -1 hydroxylase enzymes that generate 19- and 20-HETE ( 4 ). Thelatter is the putative mediator of renal autoregulation( 30 ) and tubuloglomerular feedback ( 29 ) byvirtue of its capacity to constrict PGA ( 15 ). Thesegmental distribution of 20-HETE synthetic ability in the renalvasculature demonstrates increases with decreasing vascular diameter( 17 ). Thus the most important vascular segment for regulating renal vascular resistance and glomerular function, theafferent arteriole, is most heavily invested with 20-HETE syntheticability ( 15 ).( I$ Z: L' k! w. n( x
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20-HETE has been shown to be released from PGA by ANG II viaactivation of AT 2 receptors ( 9 ). Severalmechanisms govern the tissue levels and biological activity of 20-HETE,including glucuronide conjugation ( 22 ), incorporationinto tissue phospholipids ( 3 ), and metabolism bycyclooxygenase (COX) to PG analogs that possess different biologicalproperties from 20-HETE ( 6 ). For example, in the rabbitkidney, 20-HETE produces vasodilatation, an effect abrogated byinhibition of COX, suggesting transformation of 20-HETE to PG analogspossessing vasodilator properties ( 6 )., Z! S+ r1 k1 ?3 R$ r

Stimulation of the renin-angiotensin system (RAS) has been linked toinduction of renal cortical COX-2 ( 28 ); viz,Na deprivation increased ANG II generation and inducedcortical COX-2 expression. Because ANG II stimulates release of 20-HETE from PGA ( 9 ), we explored potential interactions involving 20-HETE and COX-2, under conditions of restricted intake of salt, inmicrodissected interlobar and arcuate and interlobular arteries ofadult rats. We have reported that 20-HETE levels in incubates of renalmicrovessels, primarily afferent arterioles, of adult rats wereincreased after inhibition of COX ( 7 ).

The present study was conducted on microdissected arteries of 6- to 7-wk-old rats, because 20-HETE formation has been described to peakat this age ( 20 ). We separated interlobar arteries from arcuate and interlobular arteries to evaluate segmental variation inproduction of CYP-derived arachidonic acid (AA) metabolites. Because our preliminary study indicated the importance of COX-dependent transformation of 20-HETE ( 7 ), we determined segmentalchanges in COX-2 and COX-1 expression as well as that of / -1hydroxylase CYP4A enzymes in interlobar arteries vis a visarcuate and interlobular arteries. We found that a low-salt (LS) dietincreased release of 20-HETE from both sets of arteries, a responsethat was greater in arcuate and interlobular than interlobararteries and was associated with increased COX-2 expression in theformer. Inhibition of COX was required to demonstrate increased releaseof 20-HETE from PGA. Metabolism of 20-HETE by COX is proposed torepresent an important regulatory mechanism in the preglomerularmicrocirculation that governs arterial-arteriolar tone.# O) ]+ ^4 d8 n8 h8 P
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MATERIALS AND METHODS1 c0 x: Z0 b, E1 |& `) O* D
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Preparation of Rat Kidney Microvessels

Male Sprague-Dawley rats (between 150 and175 g) were divided into two groups, each receiving either normalsalt (NS; 0.4% NaCl; n = 28) or LS (0.05% NaCl; n = 28) for 10 days. After this treatment, rats wereanesthetized with pentobarbitol sodium (60 mg/kg). Saline-perfused (20 ml) kidneys were isolated and freed from surrounding tissue. Eachkidney was hemisected and placed in ice-cold PBS (Sigma). Interlobararteries (200-250 µm) and arcuate (100-150 µm)and interlobular (60-80 µm) arteries were isolated bymicrodissection (Fig. 1 ). Arteries(interlobar arteries and arcuate and interlobular arteries) were washedthree times with Tyrode solution (pH 7.4; Sigma) and treated asfollows.
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Fig. 1. Photomicrograph (×100 magnification) of arteriesmicrodissected from a rat kidney. The renal artery was perfused withbuffer containing iron oxide to increase vessel definition. A : interlobal arteries; B : arcuate andinterlobular arteries.

Release of 20-HETE and epoxyeicosatrienoic acids fromPGAs
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Renal vessels (interlobar arteries and arcuate andinterlobular arteries) obtained from eight pairs of NS and LS groupswere further divided into two groups, with one of them receiving either 10 µM indomethacin (Indo; Sigma) or vehicle (0.01%NaHCO 3 ) in the final wash. NADPH (1 mM; Sigma) and 7 µMof [ 14 C]AA (NEN) were added to a total of four samplesderived from each rat. The final incubation volume of each sample wasbrought up to 1 ml with oxygenated Tyrode solution. Samples wereincubated for 30 min, on the basis of our previous study, at 37°C andextracted by acidification to pH 4.0 with 9% formic acid and extractedtwice with 2× vol of ethyl acetate ( 9 ). Thesupernates were evaporated to dryness and prepared for reverse-phaseHPLC analyses. Protein concentration was determined by using theBradford method ( 1 ). Samples were purified byreverse-phase HPLC on a C 18 µ Bondapak column (4.6 × 24 mm) by using a linear gradient from acetonitrile/water/acetic acid (62.5:37.5:0.05%) to acetonitrile (100%) over 25 min at a flowrate of 1 ml/min, as previously described ( 9 ). The elution profile of the CYP-derived AA metabolites of Fig. 2 was monitored by radioactivity with anon-line radioactive detector (Radiomatic Instruments, Tampa, FL).The percent conversion of AA to radioactive peaks was calculated.
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Fig. 2. Release of 20-HETE ( A ) and epoxyeicosatrienoicacids ( B ) from arcuate and interlobular arteries and frominterlobar arteries obtained from rats fed either a normal salt (N)diet (0.4% NaCl; n = 8) or low-salt (LS) diet (0.05%NaCl; n = 8) for 10 days in the absence or presence ofindomethacin (Indo; 10 µM). Arteries were incubated with 1 mM NADPHand 7 µM [ 14 C]arachidonic acid for 30 min at 37°C.Samples were extracted and the supernates were separated byreverse-phase HPLC. Values are means ± SE. * P- @+ m8 z/ h5 k0 x, `

Western Blot Analysis of COX-1 and -2 and CYP4AProteins# k6 s" M# h* E8 W( ^! h

Tissues were lysed with 10 mM Tris · HCl(pH 7.5) and 1% SDS, followed by centrifugation at 14,000 rpm for 15 min. Protein concentrations of supernates were determined by using adetergent-compatible Bio-Rad protein assay kit. Forty micrograms ofcell lysate were mixed with an equal volume of 2× SDS-PAGE samplebuffer, separated on a 10% SDS-PAGE gel, and transferred tonitrocellulose membranes. After blocking with 5% milk, membranes wereprobed with antibodies specific for COX(s) and CYP4A [polyclonalanti-goat COX-1 and COX-2 antibodies (Santa Cruz Biotechnology) andpolyclonal anti-rabbit CYP4A antibody (Gentest)] for 1 h at roomtemperature. The membranes were washed with Tris-buffered saline withTween 20 and incubated with the appropriate horseradishperoxidase-conjugated antisera. Proteins were detected by enhancedchemiluminescence and exposed to film for visualization./ c+ U9 B0 F; W2 r5 c
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Statistical Analysis& L* u8 b6 Z- l$ g% `# y6 m

Results are expressed as means ± SE. Either a Student'stwo-sample t -test or a nonparametric two-sample rank sumtest was used to analyze differences between groups, depending onwhether assumptions of normality were met. Paired analyses (paired t -test or Wilcoxon signed-rank test) were used whencomparisons were made of data obtained from the same experimentalpreparation (i.e., arcuate and interlobular arteries vs. interlobararteries from the same kidney). Unpaired analyses (unpaired t -test or Mann-Whitney U -test) were used whencomparisons were made of data obtained from different experimentalpreparations (i.e., kidneys of NS vs. LS groups). A P valueof significant.
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RESULTS
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Release of HETEs from Renal Microvessels3 p6 U2 ~; n8 `* b  n

We had reported that rat glomerular arterioles/arteries (afferent,arcuate and interlobular, and interlobar), obtained by using the ironoxide method, generate relatively large quantities of 20-HETE andlesser quantities of 19-HETE ( 9 ). Metabolism of AA inarcuate and interlobular arteries (60- to 150-µm inner diameter) wascompared with that in interlobar arteries (200- to 250-µm innerdiameter) as affected by LS (0.05%; n = 8) vs. NS(0.4%; n = 8) intake for 10 days in the presence orabsence of Indo (10 µM) to inhibit COX. On the basis of GC-MS singleion monitoring analyses, 20-HETE was the principal product of all renalarteries/arterioles exceeding 19-HETE release by ninefold; 16-, 17-, and 18-HETEs, which have been reported to be released from the kidneyby ANG II ( 4 ), were not detected.

NS diet. Under conditions of NS intake, and in the absence of Indo, metabolismof [ 14 C]AA (7 µM) to 20-HETE, analyzed with HPLC, wassimilar in arcuate and interlobular arteries and interlobar arteries asreflected in their capacity to release 20-HETE: 30.1 ± 8.5 vs.24.6 ± 5.3 ng · mgprotein 1 · 30 min 1,respectively (Fig. 2 A ). After inhibition of COX, recovery of 20-HETE from the incubate of arcuate and interlobular arteries increased by approximately twofold, to 62.2 ± 25.0 ng · mgprotein 1 · 30 min 1 ( P was not affected (Fig. 2 A ).
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LS diet. Unless COX was inhibited, an LS diet did not increase 20-HETE levelsfrom either arcuate and interlobular or interlobar renal arteriescompared with recovery from these arteries obtained from rats on an NSdiet (Fig. 2 A ). In rats on an LS diet, addition of Indo tothe incubate containing either arcuate and interlobular or interlobararteries resulted in a two- to threefold increase in 20-HETE recovery,39.1 ± 13.2 to 101.8 ± 42.6 ng · mgprotein 1 · 30 min 1 ( P arteries, from 31.7 ± 15.1 to 61.9 ± 29.4 ng · mgprotein 1 · 30 min 1 ( P from the incubate containing PGA when COX was not inhibited(Fig. 2 A ). That is, when COX was not inhibited, recovery of20-HETE from the incubate of either arcuate and interlobular orinterlobar arteries microdissected from rats on an LS diet was reducedby ~50-60% (Fig. 2 A ). On the basis of GC-MSanalyses, the profile of CYP-HETEs formation was not altered by saltdepletion; i.e., 20-HETE was the principal HETE formed, 19-HETE beingone-ninth or less abundant (data not shown).

Release of Epoxyeicosatrienoic Acids from RenalMicrovessels
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Basal epoxyeicosatrienoic acid (EET) release from arcuate andinterlobular and interlobar arteries did not differ (Fig. 2 B ) and was comparable to basal release of 20-HETE fromthese arteries, ~20-30 ng · mgprotein 1 · 30 min 1.Moreover, vascular EET recovery was not affected by either COX inhibition or decreased salt intake (Fig. 2 B ).5 X9 D' S! E/ L4 G0 i  g) K
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Cytochrome CYP4A Hydroxylase Expression) L2 [4 N0 |  I2 f" a  w
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To determine whether changes in renal CYP4A hydroxylase expressionoccurred concomitantly with changes in release of 20-HETE from renalarteries, immunoblot analyses were conducted on arcuate andinterlobular and interlobar arteries obtained from rats subject toeither NS or LS intake for 10 days. In rats on NS intake, Western immunoblotting disclosed that CYP4A expression in arcuate and interlobular arteries was greater than that in interlobar arteries (Fig. 3 ); whereas on LS intake, CYP4Aprotein was increased only in interlobar arteries.

Fig. 3. Western immunoblot analyses of cytochrome P -450 (CYP)4A expression in renal microvessels. Top : Western immunoblot of CYP4A expression. Bottom : densitiometric analyses of CYP4A expression inarcuate and interlobular arteries and in interlobar arteries obtainedfrom rats fed either an NS diet (0.4%; n = 3) or LSdiet (0.05%; n = 3) for 10 days. Salt depletionsignificantly increases CYP4A expression in interlobar arteries. Valuesare means ± SE. * P

COX Expression
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As 20-HETE recovery from the incubate was increased by COXinhibition with Indo and as renal cortical COX-2 expression is increased by salt restriction, we examined whether COX-2 expression wasincreased in PGA in response to an LS diet. In rats fed an NS diet,COX-2 was expressed at low levels in both sets of arteries (Fig. 4 ). When dietary salt was restricted,COX-2 expression was significantly increased in arcuate andinterlobular arteries (Fig. 4 ), whereas expression of COX-1 wasunaffected by salt depletion (Fig. 5 ).

Fig. 4. Western immunoblot analyses of cyclooxygenase (COX)-2expression in renal microvessels. Top : Western immunoblot ofCOX-2 expression. Bottom : densitiometric analyses of COX-2expression in arcuate and interlobular arteries and in interlobararteries obtained from rats fed either an NS diet (0.4%; n = 3) or an LS diet (0.05%; n = 3)for 10 days. Salt depletion increased COX-2 expression in arcuate andinterlobular arteries. Values are means ± SE.* P. n+ t3 t' C$ b
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Fig. 5. Western immunoblot analyses of COX-1 expression in renalmicrovessels. Top : Western immunoblot of COX-1 expression. Bottom : densitiometric analyses of COX-1 expression inarcuate and interlobular arteries and in interlobar arteries obtainedfrom rats fed either an NS diet (0.4%; n = 3) or an LSdiet (0.05%; n = 3) for 10 days. COX-1 expression wasunaffected by salt depletion. Values are means ± SE.
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DISCUSSION
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We addressed possible links among stimulation of RAS, 20-HETEsynthesis, and induction of COX-2. As an LS diet activates RAS and asANG II increases 20-HETE release from PGA ( 9 ), we had postulated that 20-HETE released from PGA in response to an LS dietwould be increased. We quantitated CYP-AA metabolism and determinedCYP4A and COX(s) expression and activity in microdissected preglomerular arterial elements (interlobar and arcuate andinterlobular arteries) obtained from NS- and LS-treated rats. With NSintake, renal COX-2 is low in the rat kidney and was not detectedeither in PGA or glomeruli ( 28 ), whereas an LS dietenhanced 20-HETE recovery from PGA by two- to threefold and inducedexpression of CYP4A and COX-2. However, increased release of 20-HETEfrom PGA in response to an LS diet required COX inhibition to bedemonstrated, indicating that COX serves as a metabolic pathway for20-HETE by forming PG analogs of 20-HETE. These findings are inaccordance with our proposal that metabolism of 20-HETE by COX-2 actsas a braking mechanism that prevents the unopposed action of 20-HETE, apotent constrictor of renal microvessels ( 15 ). In contrast to increased formation of 20-HETE in response to an LS diet, EET production was unaffected. Increased intake of salt is reported toselectively elevate epoxygenase activity ( 2 ). The present study extends the interactions of pressor hormones with eicosanoids andsupports the concept that the coordinate interaction of -hydroxylase and COX-2 participates in the regulation of glomerular hemodynamics inLS states.

20-HETE is the principal eicosanoid in PGA ( 9 ). In theinitial studies of the renal CYP pathway, 20-HETE was reported to bethe most abundant product of renal AA metabolism in microsomes preparedfrom the whole kidney ( 24 ). 20-HETE was subsequently identified as the dominant arachidonate metabolite in crucial sitesintrarenally: afferent arterioles and contiguous microvessels, proximaltubules, and thick ascending limb ( 8, 21 ). Prominent amongthe activities of 20-HETE is its capacity in low concentrations toconstrict isolated renal arteries and arterioles ( 15, 16 ), an effect not predicted from its relatively weak vasoconstrictor actionwhen it is given to the intact kidney ( 26 ). The most compelling evidence for a pathological role for 20-HETE is in the renalfailure produced by hepatic cirrhosis (hepatorenal syndrome), which ischaracterized by intense renal vasoconstriction ( 11 ). Sacerdoti et al. ( 23 ) have shown that 20-HETE is increasedgreatly in the hepatorenal syndrome, exceeding by threefold theexcretion of thromboxane, the predominant renal COX product in patients with cirrhosis and ascites.; \; |0 ^- R' }6 I

Of the mechanisms that lower the potency of the vasoconstrictor actionof 20-HETE, thereby blunting the renal circulatory response to theeicosanoid, metabolism by COX to PG analogs ( 25 ) havingeither lesser vasoconstrictor activity or even vasodilator activity mayplay an important role under conditions of salt deprivation. The facilemetabolism of 20-HETE by COX was first recognized by Escalante et al.( 12 ), who prevented the contractile response of aorticrings to 20-HETE by either inhibition of COX or blockade of theendoperoxide/thromboxane receptor, indicating that under theseexperimental conditions 20-HETE is transformed by COX to an analog ofeither PGH 2 or thromboxane A 2.* _2 ~+ P6 r$ l: N

ANG II, in addition to promoting 20-HETE production by PGA, inducesexpression of COX-2 in the medullary thick ascending limb ( 13 ). In this instance, ANG II acts through stimulation ofTNF- to increase COX-2 activity ( 14 ). In defining the20-HETE-dependent mechanism responsible for the renal microcirculatoryresponse to salt deprivation, an essential component has beendemonstrated, viz, conversion of 20-HETE by COX-2 toproducts, PG analogs of 20-HETE ( 5 ). The coexpression ofan inducible membrane-associated PGE 2 synthase( 18 ) that acts in concert with COX-2 may favor formationof 20-OH PGE 2, a vasodilator PG analog of 20-HETE( 5 ). The capacity of COX to metabolize 20-HETE to PGanalogs, for example, 20-OH PGF 2 and 20-OHPGE 2, ( 25 ) may be critical to the modificationof the renal vascular and tubular actions of ANG II in states of saltdeprivation or abnormalities of salt and water homeostasis, such ashepatic cirrhosis, heart failure, and diabetic and hypertensivenephropathy ( 10 ). In these conditions, a largecomponent of renal blood flow is COX-2 dependent, as evidenced by theability of NSAIDs to depress renal blood flow only when pathophysiological conditions prevail, producing COX-2 expression. These factors are clearly seen when comparing the dog at rest to onechallenged by surgical stress ( 27 ). In the resting dog, Indo, even in toxic doses, does not affect renal blood flow, whereas inthe dog subject to trauma, which elevates renal PG production andplasma renin activity (via a COX-2-dependent mechanism), Indo acutelyreduces elevated renal PG levels associated with a corresponding sharpdecrease in renal blood flow.: W$ k2 c6 \5 C" [

In summary, 20-HETE recovery from PGA was shown to vary segmentally.When rats were challenged with an LS diet, arcuate and interlobulararteries exhibited the greatest release of 20-HETE, exceeding those ofinterlobar arteries under conditions of both NS and LS intake. Thesedifferences required inhibition of COX-2 to be observed, because theomission of Indo resulted in 20-HETE levels that did not differ betweenarcuate and interlobular and interlobar arteries, irrespective of saltintake (Fig. 2 ). In contrast, EET release from both small or largearteries was unaffected by either NS or LS intake, despite inhibitionof COX.8 C6 ?) m  K, q
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On the basis of the present study, we hypothesize that major adverseeffects of aspirin-like drugs may result from the direct vasoconstrictor action of 20-HETE. That is, when 20-HETE cannot betransformed to PG analogs under conditions of salt depletion, theunopposed action of 20-HETE constricts the renal vasculature. Thishypothesis has received support from the recent demonstration that twoof the principal 20-HETE PG analogs, 20-OH PGE 2 and 20-OH PGF 2, dilate the rat renal vasculature ( 5 ).The present study provides a scaffolding for examining a potentiallykey regulatory system operating within PGA, particularly whenextracellular fluid volume is contracted, initiating a compensatorymechanism involving COX-2 that mitigates the constrictor effect of20-HETE on renal microvessels.
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ACKNOWLEDGEMENTS
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We wish to acknowledge the technical assistance provided by Ben Engand also thank our colleague, Dr. Nicholas Ferreri, for his insights.We also wish to thank Dr. Praveen Chander (Department of Pathology, NewYork Medical College) for photographing the renal vessels and MelodySteinberg for editorial assistance in preparing this manuscript.
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