Glomerular podocyte injury in lifestyle-related disease : elucidation of its mechanism and establishment of novel therapeutic strategy to inhibit proteinuria

在这项研究中，我们证明了足细胞损伤的发病机制中的蛋白尿和肾小球硬化的达尔盐高血压大鼠，有效地改善选择性醛固酮受体阻滞剂依普利酮。高盐饮食喂养的醛固酮灌注大鼠表现出足细胞损伤和大量蛋白尿，依普利酮可完全逆转。肼苯哒嗪降低全身血压不能防止足细胞损伤和蛋白尿，而抗氧化剂tempol减少了损伤。在体内和体外足细胞中检测到盐皮质激素受体，醛固酮诱导其效应激酶Sgk 1，激活NADPH氧化酶和产生活性氧。我们还证实了与非肥胖SHR相比，代谢综合征模型SHR/NDmcr-cp（SHR/cp）的蛋白尿和足细胞损伤增加。SHR/cp组血清醛固酮水平和肾脏Sgk 1表达均升高。依普利酮以及tempol有效地改善足细胞损伤和蛋白尿。至于醛固酮过量的机制，从SHR/cp分离的内脏脂肪细胞分泌的物质刺激肾上腺皮质细胞的醛固酮产生。非肥胖SHR的脂肪细胞没有表现出这种活性。我们的数据表明，脂肪细胞衍生的因素可能有助于在这个模型中的醛固酮过量，足细胞损伤，和蛋白尿。最近的研究表明，足细胞损伤在糖尿病、高血压和肥胖相关的肾小球疾病中也起着致病作用。因此，醛固酮阻断可以是治疗足细胞损伤、蛋白尿、心血管和肾脏并发症的极好治疗策略。我们还证明了他汀类药物和肾上腺髓质素对足细胞损伤的保护作用。

In this study, we demonstrated the involvement of podocyte injury in the pathogenesis of proteinuria and glomerulosclerosis in Dahl salt hypertensive rats, which were effectively ameliorated by selective aldosterone blocker eplerenone. Aldosterone-infused rats fed a high salt diet demonstrated podocyte injury and massive proteinuria, which was completely reversed by eplerenone. Reduction of systemic blood pressure by hydralazine failed to prevent podocyte injury and proteinuria, whereas antioxidant tempol reduced the injury. Mineralocorticoid receptor was detected in the podocytes in vivo and in vitro, and aldosterone caused induction of its effector kinase Sgk1, activation of NADPH oxidase and generation of reactive oxygen species. We also demonstrated enhanced proteinuria and podocyte injury in metabolic syndrome model SHR/NDmcr-cp (SHR/cp) compared with non-obese SHR. Serum aldosterone level and renal Sgk1 expression were elevated in SHR/cp. Eplerenone as well as tempol effectively improved podocyte damage and proteinuria. As for the mechanisms of aldosterone excess, visceral adipocytes isolated from SHR/cp secreted substances that stimulate aldosterone production in adrenocortical cells. Adipocytes from non-obese SHR did not show such activity. Our data suggest that adipocyte-derived factors might contribute to the aldosterone excess, podocyte injury, and proteinuria in this model. Recent studies indicated that podocyte injury plays a pathogenetic role also in diabetic, hypertensive, and obesity-related glomerulopathy. Thus, aldosterone blockage can be an excellent therapeutic strategy for the treatment of podocyte injury, proteinuria, cardiovascular and renal complications in these conditions. We also demonstrated the protective actions of statins and adrenomedullin against podocyte injury.