Ghrelin improves renal function in mice with ischemic acute renal failure
Ghrelin improves renal function in mice with ischemic acute renal failure
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DOI：
10.1681/asn.2004080626
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发表时间：
2006-01-01
影响因子：
13.6
通讯作者：
Hirata, Yasunobu
中科院分区：
文献类型：
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作者：
Takeda, Ryo;Nishimatsu, Hiroaki;Hirata, Yasunobu
生长激素和IGF-1被认为具有组织保护作用。Ghrelin是一种胃源性生长激素促分泌素。观察Ghrelin对小鼠缺血再灌注性肾功能衰竭的影响。采用双侧肾动脉夹闭45 min再灌注24 h的方法复制缺血性急性肾功能衰竭模型。在手术前皮下注射Ghrelin（100 μ g/kg小鼠）或载体6次，在手术后每8小时皮下注射3次。再灌注后24小时，分离右肾并灌注。在生长激素释放肽预处理的小鼠中，乙酰胆碱（ACh）和肾上腺髓质素诱导的肾血管内皮依赖性血管舒张显著改善（10（-7）M ACh的%Delta肾灌注压-63.5 +/- 3.7 vs-41.2 +/- 5.5%; P < 0.05）。这种变化与生长激素释放肽处理小鼠肾脏中一氧化氮释放的显著增加有关（10（-7）M ACh 35.5 +/- 5.8 vs. 16.9 +/- 3.5 fmol/g肾脏/min; P < 0.05）。血清尿素氮浓度（53 +/- 7 vs 87 +/- 15 mg/dl; P < 0.05）和肾损伤评分在ghrelin组显著较低（2.5 +/- 0.8 vs 5.3 +/- 1.5; P < 0.01）。肾小管凋亡指数在ghrelin组中显著较低（5 +/-5对28 +/-4; P < 0.05）。此外，在60分钟缺血期后，Ghrelin组的存活率更高（80%对20%; P < 0.05）。Ghrelin处理显著增加血清IGF-1水平。然而，在胰岛素受体底物-2基因敲除小鼠中并未观察到胃饥饿素对缺血/再灌注损伤的肾脏保护作用。这些结果表明，生长激素释放肽可以保护肾脏缺血/再灌注损伤，这种效果是通过IGF-1介导的途径与内皮功能的改善。
Growth hormone and IGF-1 have been suggested to have tissue-protective effects. Ghrelin is a stomach-derived growth hormone secretagogue. The effects of ghrelin on ischemia/reperfusion-induced renal failure in mice were examined. Ischemic acute renal failure was induced by bilateral renal artery clamping for 45 min and reperfusion for 24 h. Ghrelin (100 mu g/kg mouse) or vehicle was injected subcutaneously six times before surgery and three times after surgery every 8 h. Twenty-four hours after reperfusion, the right kidney was isolated and perfused. Acetylcholine (ACh)- and adrenomedullin-induced endothelium-dependent vasorelaxation of renal vessels significantly improved in ghrelin-pretreated mice (%Delta renal perfusion pressure by 10(-7) M ACh -63.5 +/- 3.7 versus -41.2 +/- 5.5%; P < 0.05). This change was associated with significant increases of nitric oxide release in the kidneys of ghrelin-treated mice (10(-7) M ACh 35.5 +/- 5.8 versus 16.9 +/- 3.5 fmol/g kidney per min; P < 0.05). Serum concentration of urea nitrogen (53 +/- 7 versus 87 +/- 15 mg/dl; P < 0.05) and renal injury score were significantly lower in the ghrelin group (2.5 +/- 0.8 versus 5.3 +/- 1.5; P < 0.01). Tubular apoptotic index was significantly lower in the ghrelin group (5 +/- 5 versus 28 +/- 4; P < 0.05). Furthermore, the survival rate after the 60-min ischemic period was higher in the ghrelin group (80 versus 20%; P < 0.05). Ghrelin treatment significantly increased the serum level of IGF-1. However, such renal protective effects of ghrelin on ischemia/reperfusion injury were not observed in insulin receptor substrate-2 knockout mice. These results suggest that ghrelin may protect the kidneys from ischemia/reperfusion injury and that this effect is related to an improvement of endothelial function through an IGF-1-mediated pathway.