Role of nitric oxide (NO) and regulation of NO synthesis in the kidney.

Abstract

The general objective in undertaking this study was to determine the role of nitric oxide (NO) and neuronal nitric oxide synthase (nNOS) in the regulation of Na+ excretion by the kidney. NO regulates renal hemodynamics and induces natriuresis. The induction of Na+ excretion may be caused by either vasodilatory action of NO, and/or its direct effect on the renal tubules. Our study was the first to show that in the proximal tubule NO donors inhibit the NHE3-mediated Na+ uptake in a cGMP-dependent manner. This is an important observation since the proximal tubule is a major site of salt and water reabsorption in the kidney, and the apical NHE3 exchanger is the most important transporter of Na+ in the proximal tubule. Possible implications of these findings are for the regulation of the extracellular volume and development of hypertension. In conclusion, we have demonstrated that NO regulates Na+ uptake by directly inhibiting the NHE3 in the PT, suggesting that this could be one of the mechanisms responsible for the induction of natriuresis by NO. Our studies further demonstrated that nNOS expression in the cortex and IMCD is differentially regulated by high dietary salt, suggesting regulation from different, cell-specific promoters. In 5/6 Nx rats, we demonstrated that nNOS mRNA and protein are significantly downregulated and PIN, a specific nNOS inhibitor is upregulated, which could contribute to the overall low NO production in the kidneys of rats with CRF. Treatment with losartan had no effect on the expression of nNOS in the inner medulla of 5/6 Nx rats but reversed, in part, the inhibitory effect of 5/6 Nx on nNOS in the cortex. Furthermore, Ang II may tonically upregulate nNOS expression in the cortex and the inner medulla. (Abstract shortened by UMI.)