CYCLOOXYGENASE-2 MEDIATES INCREASED RENAL RENIN CONTENT INDUCED BY LOW-SODIUM DIET

We hypothesized that neuronal nitric oxide synthase and cyclooxygenase -2, which both exist in the renal cortex, predominantly in the macula densa, play a role in the control of renal renin tissue content. We st udied the possible role of neuronal nitric oxide synthase in regulatin g renal renin content by using mice in which the neuronal nitric oxide synthase gene has been disrupted (nNOS -/-) compared with its two pro genitor strains, the 129/SvEv and the C57BL/6, to determine if the abs ence of neuronal nitric oxide synthase would result in decreased renal renin content or blunt the increase observed during low sodium intake . Renal renin content from cortical slices was determined in adult mic e from all three strains maintained on a normal sodium diet. Renal ren in content was significantly reduced in the nNOS -/- mice compared wit h the 129/SvEv and the C57BL/6 mice (3.11+/-0.23 versus 5.66+/-0.50 an d 7.55+/-1.17 mu g angiotensin I/mg dry weight, respectively; P<.005), suggesting that neuronal nitric oxide synthase may stimulate renal re nin content under basal conditions. Neither selective pharmacological inhibition of neuronal nitric oxide synthase using 7-nitroindazole or disruption of the neuronal nitric oxide synthase gene affected the inc rease in renal renin content observed during dietary sodium restrictio n. The influence of cyclooxygenase-2 on renal renin content through a macula densa-mediated pathway was studied using a selective cyclooxyge nase-2 inhibitor, NS398, in 129/SvEv mice. A low-sodium diet increased renal renin content from 6.97+/-0.52 to 11.59+/-0.79 mu g angiotensin I/mg dry weight (P<.005); but this increase was blocked by NS398. In addition, treatment with NS398 reduced renin mRNA in response to a low -sodium diet. Thus, increased renal renin content in response to dieta ry sodium restriction appears to require the induction of cyclooxygena se-2, while neuronal nitric oxide synthase appears to affect basal but not stimulated renal renin content.