Podocyte as the target for aldosterone - Roles of oxidative stress and Sgk1
Podocyte as the target for aldosterone - Roles of oxidative stress and Sgk1
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DOI：
10.1161/01.hyp.0000255636.11931.a2
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发表时间：
2007-02-01
期刊：
影响因子：
8.3
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Shibata, Shigeru;Nagase, Miki;Fujita, Toshiro
越来越多的证据表明盐皮质激素受体阻滞剂能有效减少高血压患者的蛋白尿。然而，抗蛋白尿作用的机制仍然是难以捉摸的。在这项研究中，我们研究了醛固酮对足细胞的影响，足细胞是肾小球滤过屏障的关键参与者。单侧肾切除大鼠持续输注醛固酮，并喂以高盐饮食。醛固酮引起进行性蛋白尿，并伴有血压升高。值得注意的是，足细胞相关分子nephrin和podocin的基因表达在醛固酮输注大鼠中在2周时显著降低，此后逐渐降低。免疫组化和电子显微镜检查证实足细胞损伤。足细胞损伤伴随着肾脏减少烟酰胺腺嘌呤二核苷酸磷酸氧化酶的激活，增加氧化应激，并增强醛固酮效应激酶Sgk1的表达。依普利酮，一种选择性醛固酮受体阻滞剂，治疗，几乎完全防止足细胞损伤和蛋白尿，与正常化的升高降低烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性。此外，蛋白尿，足细胞损伤，和Sgk1的上调显着缓解tempol，膜渗透性超氧化物歧化酶，这表明氧化应激的致病作用。尽管肼苯哒嗪治疗几乎使血压正常化，但未能改善蛋白尿和足细胞损伤。在培养的足细胞与盐皮质激素受体的一致表达，醛固酮刺激减少烟酰胺腺嘌呤二核苷酸磷酸氧化酶胞质组分和氧化应激的产生足细胞的膜转位。此外，醛固酮增强Sgk 1的表达，这是由盐皮质激素受体拮抗剂和tempol抑制。总之，醛固酮灌注大鼠足细胞在早期就受到损伤，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。
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.