Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides: implications for obesity-associated hypertension.
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.
Bełtowski
Jerzy
J
Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@am.lublin.pl
Borkowska
Ewelina
E
Wójcicka
Grazyna
G
Marciniak
Andrzej
A
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase
D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D020738:Leptin; D009712:Nucleotides, Cyclic; D009569:Nitric Oxide; D010042:Ouabain; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase; D000254:Sodium-Potassium-Exchanging ATPase