Chronic hyperleptinemia induces resistance to acute natriuretic and NO-mimetic effects of leptin

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• 作者：Jerzy Beł ; towski ; Graż ; yna Wó ; jcicka ; Anna Jamroz-Wi&#x15b ; niewska ; Andrzej Wojtak
• 关键词：Leptin ; Obesity ; Arterial hypertension ; Nitric oxide ; Cyclic GMP ; Na⁺ ; K⁺-ATPase ; Natriuresis
• 刊名：Peptides
• 出版年：2010
• 出版时间：January 2010
• 年：2010
• 卷：31
• 期：1
• 页码：155-163
• 全文大小：887 K

文摘

Apart from controlling energy balance, leptin, secreted by adipose tissue, is also involved in the regulation of cardiovascular function. Previous studies have demonstrated that acutely administered leptin stimulates natriuresis and vascular nitric oxide (NO) production and that these effects are impaired in obese animals. However, the mechanism of resistance to leptin is not clear. Because obesity is associated with chronically elevated leptin, we examined if long-term hyperleptinemia impairs acute effects of leptin on sodium excretion and NO production in the absence of obesity. Hyperleptinemia was induced in lean rats by administration of exogenous leptin at a dose of 0.5 mg/kg/day for 7 days, and then acute effect of leptin (1 mg/kg i.v.) was studied under general anesthesia. Leptin increased fractional sodium excretion and decreased Na⁺,K⁺-ATPase activity in the renal medulla. In addition, leptin increased the level of NO metabolites and cyclic GMP in plasma and aortic wall. These acute effects of leptin were impaired in hyperleptinemic animals. In both control and hyperleptinemic groups the effect of leptin on Na⁺ excretion and renal Na⁺,K⁺-ATPase was abolished by phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, but not by protein kinase B/Akt inhibitor, triciribine,. In contrast, acute effect of leptin on NO metabolites and cGMP was abolished by triciribine but not by wortmannin. Leptin stimulated Akt phosphorylation at Ser⁴⁷³ in aortic tissue but not in the kidney, and this effect was comparable in control and hyperleptinemic groups. These results suggest that hyperleptinemia may mediate “renal” and “vascular” leptin resistance observed in obesity.