Angiotensin II feedback is a regulator of renocortical renin, COX-2, and nNOS expression

Salt restriction leads to parallel increases of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys. Because the upregulation of these genes is strongly enhanced if salt restriction is combined with inhibition of the renin-angiotensin-aldosterone system, our study aimed to find out whether the juxtaglomerular expressions of renin, COX-2, and nNOS are subject to a common direct negative feedback control by ANG II. For this purpose, male Sprague-Dawley rats were fed a low-salt diet (0.02% wt/wt) with or without additional treatment with the ANG I-converting enzyme (ACE) inhibitor ramipril (10 mg x kg body wt(-1) x day(-1)) for 1 wk, and renocortical renin, COX-2, and nNOS mRNAs were assayed. To narrow down possible indirect effects of the ACE inhibitor that may result from insufficient aldosterone production, the animals received mineralocorticoid substitution with fludrocortisone (6 mg. kg body wt(-1) x day(-1)). Thus mineralocorticoid substitution prevented the fall of systolic blood pressure and of glomerular filtration induced by ramipril in rats on low-salt diet. Although fludrocortisone had no effect on basal renin, COX-2, and nNOS mRNA, it clearly attenuated the threefold increases of both renin and COX-2 mRNA in response to low-salt diet. In rats on low-salt diet, ramipril further increased renin mRNA ninefold, COX-2 mRNA fourfold, and nNOS 2.5-fold in the absence of fludrocortisone. In the presence of fludrocortisone, ramipril increased renin mRNA 10-fold, COX-2 mRNA 2.5-fold, and nNOS mRNA 2.5-fold. These data indicate that mineralocorticoid substitution lowers the overall expression of juxtaglomerular renin and COX-2 during low-salt intake and attenuates a further rise of COX-2 expression by ACE inhibition, but it does not change the stimulatory effect of ACE inhibition on renin and nNOS expression. We conclude that the expression of renin, COX-2, and nNOS in the juxtaglomerular apparatus during low-salt diet is markedly limited by a direct feedback inhibition through ANG II.