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Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides: implications for obesity-associated hypertension.

Abstract
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.
AuthorsJerzy Bełtowski, Ewelina Borkowska, Grazyna Wójcicka, Andrzej Marciniak
JournalClinical and experimental hypertension (New York, N.Y. : 1993) (Clin Exp Hypertens) Vol. 29 Issue 3 Pg. 189-207 (Apr 2007) ISSN: 1064-1963 [Print] England
PMID17497345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cation Transport Proteins
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Leptin
  • Nucleotides, Cyclic
  • Nitric Oxide
  • Ouabain
  • Adenosine Triphosphatases
  • sodium-translocating ATPase
  • Sodium-Potassium-Exchanging ATPase
Topics
  • Adenosine Triphosphatases (metabolism)
  • Animals
  • Cation Transport Proteins (metabolism)
  • Disease Models, Animal
  • Enzyme Inhibitors (pharmacology)
  • Free Radical Scavengers (pharmacology)
  • Hypertension (etiology, metabolism)
  • Kidney Tubules, Proximal (drug effects, enzymology)
  • Leptin (pharmacology)
  • Male
  • Nitric Oxide (pharmacology)
  • Nucleotides, Cyclic (pharmacology)
  • Obesity (complications, metabolism)
  • Ouabain (pharmacology)
  • Rats
  • Rats, Wistar
  • Sodium-Potassium-Exchanging ATPase

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