Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Japan.
Clin Exp Nephrol. 2010 Aug;14(4):303-14. doi: 10.1007/s10157-010-0298-8. Epub 2010 Jun 9.
Recent clinical and experimental studies have shown that aldosterone is a potent inducer of proteinuria and that mineralocorticoid receptor (MR) antagonists confer efficient antiproteinuric effects. We identified glomerular epithelial cells (podocytes) as novel targets of aldosterone; activation of MR injures podocytes possibly via oxidative stress, resulting in disruption of glomerular filtration barrier, proteinuria, and progression of chronic kidney disease. We also demonstrated that SHR/cp, a rat model of metabolic syndrome, was susceptible to podocyte injury and proteinuria. Aldosterone excess caused by adipocyte-derived aldosterone-releasing factors was suggested to underlie the nephropathy. High salt intake augmented MR activation in the kidney and exacerbated the nephropathy. Furthermore, we identified an alternative pathway of MR activation by small GTPase Rac1. RhoGDIalpha knockout mice, a model with Rac1 activation in the kidney, showed albuminuria, podocyte injury, and glomerulosclerosis. Renal injury in the knockout mice was accompanied by enhanced MR signaling in the kidney despite normoaldosteronemia, and was ameliorated by an MR antagonist, eplerenone. Moreover, Rac-specific inhibitor significantly reduced the nephropathy, concomitantly with repression of MR activation. In vitro transfection studies provided direct evidence of Rac1-mediated MR activation. In conclusion, our findings suggest that MR activation plays a pivotal role in the pathogenesis of chronic kidney disease in metabolic syndrome, and that MR may be activated both aldosterone dependently (via aldosterone-releasing factors) and independently (via Rac1). MR antagonists are promising antiproteinuric drugs in metabolic syndrome, although long-term effects on renal outcomes, mortality, and safety need to be established.
最近的临床和实验研究表明，醛固酮是蛋白尿的强力诱导剂，而盐皮质激素受体（MR）拮抗剂具有有效的抗蛋白尿作用。我们发现肾小球上皮细胞（足细胞）是醛固酮的新靶标；MR 的激活可能通过氧化应激损伤足细胞，导致肾小球滤过屏障破坏、蛋白尿和慢性肾脏病进展。我们还证明，SHR/cp 是一种代谢综合征的大鼠模型，容易受到足细胞损伤和蛋白尿的影响。脂肪细胞衍生的醛固酮释放因子引起的醛固酮过多被认为是肾病的基础。高盐摄入增强了肾脏中 MR 的激活，并加重了肾病。此外，我们发现了一种小 GTP 酶 Rac1 激活 MR 的替代途径。RhoGDIalpha 敲除小鼠，一种肾脏中 Rac1 激活的模型，表现出白蛋白尿、足细胞损伤和肾小球硬化。尽管醛固酮正常，但 knockout 小鼠的肾脏损伤伴随着肾脏中 MR 信号的增强，并且用 MR 拮抗剂依普利酮可改善。此外，Rac 特异性抑制剂可显著减轻肾病，同时抑制 MR 激活。体外转染研究提供了 Rac1 介导的 MR 激活的直接证据。总之，我们的研究结果表明，MR 激活在代谢综合征慢性肾脏病的发病机制中起关键作用，MR 可能依赖于醛固酮（通过醛固酮释放因子）和独立于醛固酮（通过 Rac1）激活。MR 拮抗剂是代谢综合征中具有前景的抗蛋白尿药物，尽管需要确定其对肾脏结局、死亡率和安全性的长期影响。
