Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: Possible contribution of fat-derived factors
Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: Possible contribution of fat-derived factors
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DOI：
10.1681/asn.2006080944
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发表时间：
2006-12-01
影响因子：
13.6
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Nagase, Miki;Yoshida, Shigetaka;Fujita, Toshiro
代谢综合征是蛋白尿和慢性肾脏疾病的重要危险因素，与糖尿病和高血压无关;然而，其潜在机制尚未阐明。醛固酮参与肥胖相关疾病的靶器官损伤。本研究探讨了醛固酮在17周龄SHR/NDmcr-cp（一种代谢综合征大鼠模型）早期肾病中的作用。与非肥胖SHR相比，SHR/NDmcr-cp中蛋白尿显著，并伴有足细胞损伤，足突消失、结蛋白诱导和nephrin衰减证明了这一点。SHR/NDmcr-cp组血清醛固酮水平、肾脏和肾小球醛固酮效应激酶Sgk 1表达以及氧化应激标志物均升高。肾小球足细胞表达盐皮质激素受体。依普利酮，一种选择性醛固酮阻滞剂，有效地改善足细胞损伤，蛋白尿，Sgk 1和氧化应激。抗氧化剂tempol也减轻足细胞损伤和蛋白尿，沿着抑制Sgk 1。至于醛固酮过量的机制，从SHR/NDmcr-cp分离的内脏脂肪细胞分泌刺激肾上腺皮质细胞中醛固酮产生的物质。坎地沙坦不抑制脂肪细胞释放醛固酮的活性。非肥胖SHR的脂肪细胞没有显示出这种活性。总之，SHR/NDmcr-cp表现出增强的醛固酮信号传导、足细胞损伤和蛋白尿，依普利酮或tempol可改善这些情况。这些数据还表明，脂肪细胞衍生的因子以外的血管紧张素II可能有助于该模型的醛固酮过量。
Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.