标题: Role of macula densa cyclooxygenase-2 in renovascularhypertension [打印本页] 作者: 轻羽 时间: 2009-4-21 13:50 标题: Role of macula densa cyclooxygenase-2 in renovascularhypertension
作者：AndreaHartner, NadaCordasic, MargareteGoppelt-Struebe, RolandVeelken, Karl F.Hilgers作者单位：Department of Medicine IV, University ofErlangen-Nürnberg, 91054 Erlangen, Germany 5 O& [( \$ t, `7 K J ! s4 M& M9 @% h% \ G( W
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& { I) k: v7 t- f 【摘要】 4 A8 Y7 g6 p+ u: F: i$ A Upregulation of the induciblecyclooxygenase (COX-2) in the macula densa accompanies theactivation of the juxtaglomerular apparatus in many high-reninconditions. The functional role of COX-2 in these disease states ispoorly understood. We tested whether COX-2 is required to increaserenin in renovascular hypertension. Rats with established two-kidney,one-clip (2K1C) hypertension were treated for 2 wk with two differentinhibitors of COX-2, NS-398 and rofecoxib, respectively. Hypertensionin 2K1C rats was not affected or slightly enhanced by COX-2 inhibition,as measured intra-arterially in conscious animals. The increase in plasma renin activity was also unchanged by both rofecoxib and NS-398.The number of glomeruli with a renin-positive juxtaglomerular apparatuswas elevated in clipped kidneys and decreased in contralateral kidneysof 2K1C rats. This pattern was unaltered by COX-2 inhibition. To testthe effects of COX-2 blockade on a primarily macula densa-mediated stimulus, we studied salt depletion for comparison. A low-salt dietinduced a significant increase in plasma renin activity, which waspartially inhibited by treatment with NS-398. We conclude thatinhibition of COX-2 in established renovascular hypertension does notaffect renin synthesis or release. Thus either COX-2 is not necessaryfor the macula densa mechanism or the macula densa is not important formaintaining high renin in renovascular hypertension. ( ]& Y. I8 N3 F2 D% q, J* `6 J ( d. U L! u/ l* C. n! m- ^2 f% }
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two-kidney, one-clip; renin expression; renin-angiotensin system; plasma renin activity; NS-398; rofecoxib ; [2 ^! i4 ]: v& ^; ?
【关键词】 cyclooxygenase renovascularhypertension! M0 L( P0 V; n& Y
INTRODUCTION - V& s) f6 K& o2 F# `/ q$ ^ - x4 k, e1 e7 E; c6 g7 _CYCLOOXYGENASES (COXs) are key enzymes in the generation of prostaglandins, which areinvolved in the regulation of renin in the kidney ( 10 ). Inparticular, renal expression of COX-2 has attracted the attention ofmany hypertensiologists, as it is localized in the macula densa cellsof the thick ascending limb of Henle ( 5, 6 ). Furthermore,macula densa COX-2 is upregulated by low-sodium intake( 5 ), low perfusion pressure ( 6 ), andinhibition of the renin-angiotensin system ( 21 ), suggesting an involvement of COX-2 in the macula densa mechanism. Indeed, some authors have reported that selective inhibition of COX-2reduced the increase in renal renin induced by salt depletion ( 4 ) and angiotensin inhibition ( 3 ). On theother hand, controversial findings were reported by others who foundthat the increase in renin induced, for example, by angiotensininhibition was not dependent on COX-2 activity ( 9 ).6 O* Q9 t) v; V" U
: g1 l! w9 p7 pOur laboratory reported a coordinate increase in COX-2 and renin in thejuxtaglomerular apparatus of the poststenotic kidney in renovascularhypertension ( 6 ). This finding supported the notion thatprostaglandins generated by COX-2 may contribute to the regulation ofrenin in renovascular hypertension: synthesis and release of the enzymeare stimulated in the poststenotic kidney but decreased in thecontralateral kidney ( 17 ). Previous experiments withnonselective COX inhibitors were compatible with this notion ( 16 ). However, controversial findings were subsequentlyreported with specific blockers of COX-2: the increase in renin in the poststenotic kidney was blocked in aortic coarctation ( 20 )but not in an acute model of renal artery stenosis ( 14 ).One possible explanation for these apparently controversial findings isthat the role of the macula densa mechanism may differ relative to other mechanisms of renin regulation. For example, a strong stimulation of the baroreceptor mechanism in acute renal artery stenosis may overrun the macula densa mechanism., k& a; J- d1 s- Y2 i# _/ z) @
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To clarify the role of macula densa COX-2 in the maintenance phase ofrenovascular hypertension, we measured kidney renin content and releaseafter inhibition of COX-2 in established Goldblatt hypertension[2-kidney, 1-clip (2K1C)] in rats with the selective COX-2 blockersNS-398 and rofecoxib. 3 r/ P: y' {6 p" \ . m% u1 {2 n2 W8 eMETHODS& N- t& _1 L1 F7 k8 e1 A! {
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Induction of hypertension. All procedures performed in animals were done in accordance withguidelines of the American Physiological Society. 2K1C renovascular hypertension was induced in male Sprague-Dawley rats weighing 150-170 g as described previously ( 6, 13 ). Controlanimals were sham operated. The animals were followed by weeklymeasurements of weight and systolic blood pressure by tail-cuffplethysmography. In contrast to the model used by Mann et al.( 14 ), lower perfusion pressure of the poststenotic kidneydoes not occur immediately after the procedure but develops slowly withthe growth of the animal over a period of at least 1 wk. Animals wereonly included into the 2K1C groups if systolic blood pressure was above150 mmHg. Animals that failed to thrive or lost weight were excluded after 2 wk.$ T. O( l1 h7 o9 P, J& Z
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COX-2 inhibition with NS-398 or rofecoxib. Six 2K1C and six control rats then received the COX-2 inhibitor NS-398for another 2 wk at a concentration of 10 µg/ml in the drinkingwater. Based on the animals' drinking behavior, the approximate dosetaken up was 1 mg · kg 1 · day 1.Six 2K1C and six controls received solvent (0.3% ethanol) only. In aseperate set of experiments, 2K1C hypertension was induced as describedabove. After 2 wk, six 2K1C and five sham-operated animals were treatedwith 10 mg · kg 1 · day 1 rofecoxib (Vioxx solution; MSD, Munich, Germany) by daily gavage for 14 days. Six 2K1C and five sham-operated controls received solvent (43 gsorbitol and xanthan gum in 100 ml tap water) by daily gavage. BothCOX-2 blockers at the doses used have been shown to be effective in thekidney ( 11, 12, 18 ). 0 H% o3 j% j) z ! P7 B- [$ ~5 i: d3 wMeasurement of arterial blood pressure. Four weeks after clipping, the animals were equipped with a femoralartery catheter under ketamine/xylazine anesthesia, and intra-arterialblood pressure was measured in conscious rats 4 h after anesthesiavia a transducer connected to a polygraph (Hellige, Freiburg, Germany).6 u( o1 F9 @) @% L, L
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Collection of blood and tissue material. Blood was taken from arterial catheters for quantification of plasmarenin activity. Animals were then killed by dissecting the abdominalartery and bleeding under deep ketamine/xylazine anesthesia. Afterkidney weight was measured, the organs were decapsulated. Kidneys wereput in methyl-Carnoy's solution (60% methanol, 30% chloroform and10% glacial acetic acid) for fixation.+ I. A# `' R2 y: k7 b; i
* R$ q0 t) B( |/ L* dPlasma renin activity. Plasma renin activity was assessed by determination of the conversionof angiotensinogen to angiotensin I. Angiotensin I was measured byradioimmunoassay after incubation at 37°C for 1 h ( 13 ).9 ^; z) t2 k% b5 j0 P
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Salt depletion. To test the effects of COX-2 blockade on a primarily maculadensa-mediated stimulus, we studied salt depletion for comparison. Eight rats received a low-salt diet (0.08% NaCl), and four rats received a normal-salt diet (0.6% NaCl) for 10 days. At the same time,four of the low-salt-treated rats received ~1mg · kg 1 · day 1 of NS-398 via the drinking water. Plasma renin activity was also measured in these animals. ; h0 ~% y4 d0 S9 H+ x6 T0 A5 s6 P- K4 o: H+ O
Immunohistochemistry for renin and COX-2. After overnight fixation in methyl-Carnoy's solution, tissues weredehydrated by bathing in increasing concentrations of methanol, followed by 100% isopropanol. After being embedded in paraffin, 3-µmsections were cut with a Leitz SM 2000R microtome (Leica Instruments,Nussloch, Germany). Before any staining procedure was conducted,sections were deparaffinized and rehydrated, and endogenous peroxidaseactivity was blocked. Detection of renin and COX-2 was performed asdescribed previously ( 6, 7 ). The Vectastain DAB kit(Vector Laboratories, Burlingame, CA) was used as a chromogen. Theprimary antibodies used were 1 ) polyclonal antiserum 8914 todetect rat renin (a generous gift from Walter Fischli, Actelion,Allschwil, Switzerland) in a dilution of 1:2,000 and 2 ) apolyclonal antibody to COX-2 (M-19, Santa Cruz Biotechnology, Heidelberg, Germany) in a dilution of 1:500. The specificity of theantibodies used was confirmed as described before ( 6 ).( A1 K' i, Q* I4 t8 H( g
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Data analysis. Quantification of renin or COX-2 expression was performed by countingthe number of glomeruli with an adjacent juxtaglomerular apparatusstaining positive for COX-2 or renin, respectively (see Fig. 4 ). Ineach kidney, 100-200 glomeruli were counted, and the number ofpositive glomeruli was expressed as a percentage of the total number ofglomeruli counted. These percent values were used for statisticalanalysis. Two-way analysis of variance, followed by a post hocNewman-Keuls test, was used to test the significance of differencesbetween groups. A P value significant. Procedures were carried out using SPSS software (release 9.01, SPSS, Chicago, IL). Values are displayed as means ± SE. [, _- I7 p+ J' ^; i( w+ i. M# d) R& C: {
RESULTS 7 X, d# Z' e3 J- L: y2 P# m* M% n4 I; U$ ~8 P) W
Mean arterial pressure was significantly increased by renal arteryclipping in both sets of experiments as measured 4 wk after placementof the clip (Fig. 1, A and B ). This increase could be detected in vehicle-treated and COX-2 inhibitor-treated rats alike. Administration of NS-398 (estimated dose: 1 mg · kg 1 · day 1 )had no effect on mean arterial pressure, either in sham-operated or in2K1C animals (Fig. 1 A ). Treatment with rofecoxib even led toa slight elevation of mean arterial blood pressure, which did not reachstatistical significance (Fig. 1 B ). 6 s- S, t9 a, Z6 B/ y" V! B; k; E. U& `8 s
Fig. 1. Mean arterial pressure measured in conscious rats 4 wkafter renal artery clipping [2 kidney, 1 clip (2K1C)] or shamoperation (sham) with or without cyclooxygenase-2 (COX-2) inhibition byNS-398 ( A ) or rofecoxib ( B ). Values aremeans ± SE. There were no significant differences betweentreatment with COX-2 inhibitors and solvent. * Significantdifferences between sham operation and 2K1C, P3 S( ?' ^& E7 W. `- W7 x1 g$ h2 V$ D
3 K* t9 L: Q: b* y$ H+ }Similar effects were observed with regard to plasma renin activity:2K1C increased plasma renin activity significantly in both sets ofexperiments (Fig. 2, A and B ). Administration of theCOX-2 inhibitors NS-398 or rofecoxib had no significant effect onplasma renin activity, either in sham-operated or in 2K1C animals (Fig. 2, A and B ). 5 @8 B2 N* N5 v) H) X7 m* f 9 U; C" w# x$ {( bFig. 2. Plasma renin activity (PRA) measured in samples fromconscious 2K1C and sham rats with or without COX-2 inhibition by NS-398( A ) or rofecoxib ( B ). Values are means ± SE. There were no significant differences between treatment with COX-2inhibitors and solvent. * Significant differences between sham and2K1C rats, P 4 M n1 l( e) c" t5 ]1 [ ; L5 n. S1 V# s/ EAs a control for the activity of the COX-2 inhibitor NS-398, plasmarenin activity was determined in salt-depleted rats with and withouttreatment with NS-398. A low-salt diet for 10 days significantlyincreased plasma renin activity, which was partly reduced by treatmentwith the COX-2 inhibitor (Fig. 3 ).; H: L9 R. q) Y8 _1 c" l8 g$ y6 s
8 b% j" z/ Q! F+ u hFig. 3. Plasma renin activity (PRA) measured in samples fromconscious rats after 10 days of a low-salt (0.08% NaCl) diet with orwithout treatment with NS-398 or a normal-salt (0.6% NaCl) diet.Values are means ± SE. * P) s; r7 ?9 W% Y* m
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The number of glomeruli with a renin-positive juxtaglomerular apparatus(Fig. 4 A ) was increased inclipped kidneys of 2K1C rats and decreased in contralateral nonclippedkidneys of 2K1C rats compared with sham-operated animals. NeitherNS-398 nor rofecoxib had an effect on the number of glomeruli with arenin-positive juxtaglomerular apparatus (Fig. 5, A and B ). : B$ J% u& p# o0 m! j9 ] $ B+ s2 A8 z0 G7 xFig. 4. Immunohistochemical localization of renin ( A )or COX-2 ( B ) in clipped kidneys of 2K1C rats. Positive reninstaining was observed in the media of afferent arterioles, while COX-2was detected in cells of the macula densa. C : absence ofrenin immunoreactivity in most of the juxtaglomerular apparatus ofcontralateral kidneys. s& a( x8 i$ L t & ~3 Z7 `4 L# g6 f) y: V. b) [Fig. 5. Quantification of kidney renin staining 4 wk after renalartery clipping or sham operation with or without COX-2 inhibition byNS-398 ( A ) or rofecoxib ( B ). The no. of glomeruliwith a renin-positive juxtaglomerular apparatus is expressed as apercentage of all counted glomeruli. Values are means ± SE. Therewere no significant differences between COX-2 inhibition and solvent.* Significant differences between 2K1C (clipped or contralateralkidney, respectively) and sham operation, P ; u! l) @ q" P: b* x$ `0 s; I 2 ~ X Z, o: F4 J3 nTo rule out a potential effect of a COX-2 inhibitor on the abundance ofCOX-2 in the kidney, the number of glomeruli with COX-2-positive maculadensa cells (Fig. 4 B ) was counted. As expected, COX-2staining was increased in clipped kidneys compared with sham-operatedrats. However, NS-398 had no significant effect on COX-2immunoreactivity (Fig. 6 ). * O% R! `7 w7 Y! Q* X1 M8 `1 W7 C* e+ b6 O
Fig. 6. Quantification of kidney COX-2 staining 4 wk after renalartery clipping or sham operation. The no. of glomeruli with aCOX-2-positive juxtaglomerular apparatus is expressed as a percentageof all counted glomeruli. Values are means ± SE. There were nosignificant differences between NS-398 and solvent. 5 D( x* G9 r! O& B5 Q' b 2 T4 v# P3 z- `/ t( S% x7 ?DISCUSSION " b) W5 @. ~" j' x- D0 w9 s5 `% N5 }+ A3 U, c
Our results show that in established 2K1C hypertension, COX-2blockade had no effect on the increase in blood pressure or on plasmarenin activity. Moreover, NS-398 or rofecoxib did not alter theincrease in renin immunoreactivity in clipped kidneys or the decreasein renin immunoreactivity in the contralateral kidneys of 2K1Chypertensive rats. This observation was surprising, because in aprevious study we had shown a regulation of COX-2, which correlatedwith renin in this model ( 6 ). Evidence against a causallink between COX-2 and renin was also reported from a model of acuterenal artery stenosis. Treatment with the COX-2 inhibitor celecoxib didnot change renin expression in this model ( 14 ).3 l- L0 _7 J/ o/ ~0 ?
% }7 w+ s4 ?- T$ ]8 W' vIn another model of renovascular hypertension, however, the COX-2inhibitor SC-58236 was found to decrease renin production and release( 20 ). We do not know whether the differences between thatstudy and our findings are due to the different models of renovascularhypertension or to the different drugs used. Although we did notdirectly assess blockade of renal COX-2 activity, both inhibitors usedin our study were applied in concentrations that had been shown beforeto inhibit renal COX-2 activity ( 11, 12, 18 ). A dose of 1 mg · kg 1 · day 1 NS-398 has been shown to reduce prostaglandin E 2 releasefrom rat kidney by 20-30%, which is approximately the percentagethat can be ascribed to COX-2 ( 18 ). A dose of 10 mg · kg 1 · day 1 rofecoxib has been shown to abolish the diuretic-induced,COX-2-mediated increase in urinary prostaglandin E 2 andF 1 ( 11 ). On the other hand, SC-58236, whichwas given by Wang et al. ( 20 ) for 1 wk, has a half-life of~5 days in rats ( 15 ). A dose of 10 mg/kg for 7 daysresults in a cumulative dose that might well reach the IC 50 of SC-58236 for COX-1 in plasma (17.8 nmol/ml). Whether or not thesubstance further accumulates in the kidney is unknown, but additionalinhibition of COX-1 cannot be ruled out after the dosage given by Wanget al. ( 20 ). 6 Z D) x' q; j, z 7 {0 o4 l" B: E2 `Stimulation of plasma renin activity by a low-sodium diet, however, wasattenuated by the COX-2 inhibitor NS-398, indicating that NS-398 infact exerted a functional effect on COX-2 activity, leading to apartial blockade of the macula densa mechanism. These data agree withsome results on the role of COX-2 in the regulation of renin. Aninhibitory effect of COX-2 blockade with NS-398 on low-salt-inducedrenin secretion was shown in a model of isolated perfusedjuxtaglomerular apparatus ( 19 ). Furthermore, inhibition oflow-salt-induced renin activity by NS-398 was demonstrated by Hardinget al. ( 4 ). Similarly, rofecoxib attenuated the stimulation of renin by a low-salt diet in the same concentrations thatwere used in our study ( 12 ). NS-398 was also efficient inattenuating the stimulation of renin secretion in response to the loopdiuretic bumetanide, which blocks macula densa salt transport( 2 ). In accordance with this concept, renin activation bya low-salt diet was markedly attenuated in COX-2 knockout mice ( 22 ). When these findings are taken together, there is nowgood evidence for a role of COX-2-derived prostaglandins in theregulation of renin in response to salt load. / M6 X4 D. Y2 t4 H8 s2 G 8 K6 w. o d7 C4 g7 Z2 g3 NOther mechanisms could be implicated in the regulation of renal reninin response to renal artery stenosis. The expression of the neuronalnitric oxide synthase in the macula densa was regulated in parallel torenin in the juxtaglomerular apparatus after renal artery stenosis( 1 ). Two other possible mechanisms involved in theregulation of renin stimulation are the baroreceptor mechanism andrenal nerve activity. Interestingly, the latter seems to be requiredfor stimulation of cortical neuronal nitric oxide synthase expressionduring salt deficiency but not for stimulation of renin or COX-2expression in this model ( 8 ). - {6 r& H; m- p* ]6 j. y3 i m/ `- `: Z" K$ O7 v+ K4 m" s2 D
We speculate that the most likely explanation of our findings isthat the macula densa mechanism for renin release is blocked to somedegree by COX-2 inhibition but that this mechanism is not absolutelyrequired for the regulation of renin in renovascular hypertension.Other mechanisms, in particular the baroreceptor mechanism, may mediaterenin regulation under these conditions even if the function of themacula densa is impaired.: B$ q1 x) I6 `5 l
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ACKNOWLEDGEMENTS 5 a4 {5 p$ c2 Z3 N5 F8 |0 b5 T! D1 I/ }
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8 F' Z2 X/ w; {6 _/ `) b " Z7 Z. d; ^$ T1 R( ~$ D : s9 J8 J+ R9 H+ z ]4 z22. Yang, T,Endo Y,Huang YG,Smart A,Briggs JP,andSchnermann J. Renin expression in COX-2-knockout mice on normal or low-salt diets. Am J Physiol Renal Physiol 279:F819-F825,2000 .作者: 张佳 时间: 2015-6-5 12:18