Interactions of the renin-angiotensin system and neuronal nitric oxide synthase in regulation of cyclooxygenase-2 in the macula densa.
Cyclooxygenase-2 (COX-2) expression in rat kidney is localized to the macula densa and the immediately proximal cTALH and increases after salt restriction. Either ACE inhibitors or AT1 receptor blockers increase COX-2 expression in both control and salt-restricted animals, suggesting that the RAS activation feedback inhibits renal cortical COX-2 expression. To determine whether increased COX-2 expression in response to ACE inhibition mediated increases in renin production, rats were treated with Captopril for 1 week with or without the specific COX-2 inhibitor, SC58236. Plasma renin activity increased significantly in the Captopril group. This increase was partially reversed by simultaneous treatment with SC58236. Kidney renin activity also increased in the Captopril group compared with control, which was also significantly inhibited by SC58236 treatment. Because of the localization of bNOS to MD and surrounding cTALH, the current study investigated the role of NO in the regulation of COX-2 expression. Rats were fed a normal diet, low salt diet or low salt diet combined with captopril and half of them were treated with the neuronal NOS inhibitor, 7-NI, and half with vehicle. After 7 days, mRNA was extracted and the microsome proteins purified from renal cortex. COX-2 mRNA expression was measured by Northern-blot and normalized with GAPDH. 7-NI treatment decreased COX-2 mRNA and immunoreactive COX-2 expression in each group. In summary, these studies indicate that COX-2 from macula densa/cTALH is a regulator of renin production and release. Angiotensin II may be a negative regulator of cTALH/macula densa COX-2 expression, and NO may mediate increased renal cortical COX-2 expression seen in volume depletion. These studies suggest important interactions between the NO and COX-2 systems in the regulation of arteriolar tone and the renin-angiotensin system by the macula densa.
Harris
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George M. O'Brien Kidney and Urologic Diseases Center and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Cheng
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Wang
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Zhang
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McKanna
J A
JA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004039:Diet, Sodium-Restricted; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012084:Renin-Angiotensin System / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007191:Indazoles; D007527:Isoenzymes; D012333:RNA, Messenger; D002956:Citrulline; D002216:Captopril; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013890:Thiourea; C086717:S-methylthiocitrulline; C080122:7-nitroindazole