Autocrine Inhibition of Renal Epithelial -ATPase by Nitric Oxide.

Nitric oxide (NO) exerts natriuretic effects independently of its hemodynamic actions. The mechanisms of this natriuresis are not yet completely understood. Induction of NO synthase by cytokines in mouse proximal tubule epithelium is followed by a 40% reduction in -ATPase activity and Na+-dependent solute transport. This inhibition is prevented by Nω-nitro L-arginine and L-arginine depletion, and mimicked by the NO donors sodium nitroprusside (SNP) and SIN-1. The mechanisms of this inhibitory effect appear to involve cGMP since 8-pCPT-cGMP partially inhibits -ATPase activity. However, superoxide dismutase prevents the autocrine inhibition of -ATPase by NO suggesting that peroxynitrite plays an important role in this process. Alterations of the redox state to favor the production of free nitric oxide species (NO ) and hence, peroxynitrite, from SNP results in more pronounced inhibition of -ATPase activity. Conversely, S-nitrosocysteine, a predominantly nitrosonium ion (NO+) donor, causes only minimal inhibition of pump activity. Taken together, these observations indicate that NO generated following the induction of proximal tubule epithelium NO synthase inhibits ATPase activity in an autocrine fashion by mechanisms involving, in part cGMP, but predominantly peroxynitrite formation. This inhibition is accompanied by a corresponding reduction in Na+-dependent solute transport and may play an important role in mediating the natriuretic effects of NO.