This study examined the effect of
leptin on renal
ouabain-resistant
Na(+)-ATPase, which drives the reabsorption of about 10% of
sodium transported in the proximal tubule. Chronic
leptin administration (0.25 mg/kg s.c. twice daily for seven days) increased
Na(+)-ATPase activity by 62.9%. This effect was prevented by the coadministration of
superoxide dismutase mimetic,
tempol, or the
NADPH oxidase inhibitor,
apocynin (2 mM in the
drinking water). Acutely administered NO donors decreased
Na(+)-ATPase activity. This effect was abolished by
soluble guanylate cyclase inhibitor, ODQ, but not by
protein kinase G inhibitors. Exogenous cGMP reduced
Na(+)-ATPase activity, but its synthetic analogues,
8-bromo-cGMP and
8-pCPT-cGMP, were ineffective. The inhibitory effect of NO donors and cGMP was abolished by
EHNA, an inhibitor of cGMP-stimulated
phosphodiesterase (PDE2). Exogenous cAMP analogue and dibutyryl-cAMP increased
Na(+)-ATPase activity and abolished the inhibitory effect of cGMP. Finally, the administration of
superoxide-generating mixture (
xanthine oxidase+hypoxanthine) increased
Na(+)-ATPase activity. The results suggest that
nitric oxide decreases renal
Na(+)-ATPase activity by stimulating cGMP, which in turn activates PDE2 and decreases cAMP concentration. Increased production of
reactive oxygen species may lead to the elevation of
Na(+)-ATPase activity by scavenging NO and limiting its inhibitory effect. Chronic hyperleptinemia is associated with increased
Na(+)-ATPase activity due to excessive oxidative stress.