Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides:: Implications for obesity-associated hypertension
Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides:: Implications for obesity-associated hypertension
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DOI：
10.1080/10641960701361585
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发表时间：
2007-04-01
影响因子：
12.3
通讯作者：
Marciniak, Andrzej
中科院分区：
文献类型：
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作者：
Beltowski, Jerzy;Borkowska, Ewelina;Marciniak, Andrzej
这项研究检查了瘦素对肾哇巴因抗性 Na+-ATP 酶的影响，该酶驱动近端肾小管中约 10% 转运的钠的重吸收。长期施用瘦素（0.25 mg/kg，皮下注射，每天两次，持续 7 天）可使 Na+-ATP 酶活性增加 62.9%。通过同时使用超氧化物歧化酶模拟物 tempol 或 NADPH 氧化酶抑制剂夹竹桃麻素（饮用水中 2 mM）可防止这种效应。急性NO供体减少Na+-ATP酶活性。这种效应可以被可溶性鸟苷酸环化酶抑制剂 ODQ 消除，但不能被蛋白激酶 G 抑制剂消除。外源cGMP降低Na+-ATP酶活性，但其合成类似物8-溴-cGMP和8-pCPT-cGMP无效。 NO 供体和 cGMP 的抑制作用被 EHNA（一种 cGMP 刺激的磷酸二酯酶 (PDE2) 抑制剂）消除。外源性cAMP类似物和二丁酰-cAMP可增加Na+-ATP酶活性并消除cGMP的抑制作用。最后，施用产生超氧化物的混合物（黄嘌呤氧化酶+次黄嘌呤）增加了Na+-ATP酶活性。结果表明，一氧化氮通过刺激 cGMP 降低肾脏 Na+-ATP 酶活性，进而激活 PDE2 并降低 cAMP 浓度。活性氧产生的增加可能会清除 NO 并限制其抑制作用，从而导致 Na+-ATP 酶活性升高。慢性高瘦素血症与过度氧化应激导致的 Na+-ATP 酶活性增加有关。
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.