Ghrelin Improves Renal Function in Mice with Ischemic Acute Renal Failure

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Abstract
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 μg/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 (%Δ 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.