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

被引:28
作者
Beltowski, Jerzy [1 ]
Borkowska, Ewelina [1 ]
Wojcicka, Grazyna [1 ]
Marciniak, Andrzej [1 ]
机构
[1] Med Univ Lublin, Dept Pathophysiol, PL-20090 Lublin, Poland
关键词
leptin; obesity; arterial hypertension; Na+-ATPase; nitric oxide; reactive oxygen species;
D O I
10.1080/10641960701361585
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 adininistered 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.
引用
收藏
页码:189 / 207
页数:19
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