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 macul a densa and the immediately proximal cTALH and increases after salt restric tion. Either ACE inhibitors or AT(1) receptor blockers increase COX-2 expre ssion 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 i ncreases in renin production, rats were treated with Captopril for 1 week w ith or without the specific COX-2 inhibitor, SC58236. Plasma renin activity increased significantly in the Captopril group. This increase was partiall y reversed by simultaneous treatment with SC58236. Kidney renin activity al so increased in the Captopril group compared with control, which was also s ignificantly 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, l ow 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. Afte r 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 e xpression in each group. In summary, these studies indicate that COX-2 from macula densa/cTALH is a regulator of renin production and release. Angiote nsin 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 volum e depletion. These studies suggest important interactions between the NO an d COX-2 systems in the regulation of arteriolar tone and the renin-angioten sin system by the macula densa.