Shibata Shigeru, Nagase Miki, Yoshida Shigetaka, Kawachi Hiroshi, Fujita Toshiro
Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Hypertension. 2007 Feb;49(2):355-64. doi: 10.1161/01.HYP.0000255636.11931.a2. Epub 2007 Jan 2.
Accumulating evidence suggests that mineralocorticoid receptor blockade effectively reduces proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with aldosterone and fed a high-salt diet. Aldosterone induced proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules nephrin and podocin were markedly decreased in aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of aldosterone effector kinase Sgk1. Treatment with eplerenone, a selective aldosterone receptor blocker, almost completely prevented podocyte damage and proteinuria, with normalization of elevated reduced nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition, proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by tempol, a membrane-permeable superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although hydralazine treatment almost normalized blood pressure, it failed to improve proteinuria and podocyte damage. In cultured podocytes with consistent expression of mineralocorticoid receptor, aldosterone stimulated membrane translocation of reduced nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore, aldosterone enhanced the expression of Sgk1, which was inhibited by mineralocorticoid receptor antagonist and tempol. In conclusion, podocytes are injured at the early stage in aldosterone-infused rats, resulting in the occurrence of proteinuria. Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.
越来越多的证据表明，盐皮质激素受体阻断可有效降低高血压患者的蛋白尿。然而，其抗蛋白尿作用的机制仍不清楚。在本研究中，我们研究了醛固酮对足细胞（肾小球滤过屏障的关键组成部分）的影响。将单侧肾切除的大鼠持续输注醛固酮并给予高盐饮食。醛固酮逐渐诱导蛋白尿，伴有血压升高。值得注意的是，在输注醛固酮的大鼠中，足细胞相关分子nephrin和podocin的基因表达在2周时显著降低，此后逐渐下降。免疫组织化学研究和电子显微镜证实了足细胞损伤。足细胞损伤伴随着肾脏还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶激活降低、氧化应激增加以及醛固酮效应激酶Sgk1表达增强。用选择性醛固酮受体阻滞剂依普利酮治疗几乎完全预防了足细胞损伤和蛋白尿，同时使升高的还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性恢复正常。此外，膜通透性超氧化物歧化酶tempol可显著减轻蛋白尿、足细胞损伤和Sgk1上调，提示氧化应激的致病作用。虽然肼屈嗪治疗几乎使血压恢复正常，但未能改善蛋白尿和足细胞损伤。在盐皮质激素受体表达一致的培养足细胞中，醛固酮刺激足细胞中还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶胞质成分的膜转位和氧化应激产生。此外，醛固酮增强了Sgk1的表达，而盐皮质激素受体拮抗剂和tempol可抑制该表达。总之，在输注醛固酮的大鼠中，足细胞在早期受到损伤，导致蛋白尿的发生。醛固酮可能通过诱导氧化应激和Sgk1直接调节足细胞功能。
