mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice
mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice
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DOI：
10.1172/jci44771
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Inoki, Ken;Mori, Hiroyuki;Guan, Kun-Liang
糖尿病肾病是1型和2型糖尿病患者发生的最致命的并发症之一。足细胞功能障碍被认为是包括糖尿病肾病在内的肾小球疾病中与蛋白尿和肾小球硬化相关的关键事件。然而，糖尿病肾病发病过程中足细胞功能障碍的分子机制尚不清楚。在这里，我们已经证明，在糖尿病动物的足细胞中，mTOR复合体1(MTORC1)的活性增强，这是一种感知营养可获得性的激酶。此外，消融上游负调控因子(PcKOTsc1)诱导的足细胞特异性mTORC1激活概括了许多糖尿病肾病的特征，包括非糖尿病幼年和成年小鼠的足细胞丢失、肾小球基底膜增厚、系膜扩张和蛋白尿。MTORC1的异常激活导致了裂隙横隔膜蛋白的错误定位，并诱导了足细胞上皮-间充质转化样表型转换，从而增强了内质网应激。相反，在PcKOTsc1小鼠中，使用化学伴侣减轻内质网应激显著防止足细胞表型转换和足细胞丢失。最后，糖尿病动物足细胞特异性mTORC1的基因减少抑制了糖尿病肾病的发展。这些结果表明，足细胞mTORC1激活是糖尿病肾病发生的关键事件，降低足细胞mTORC1活性是预防糖尿病肾病的一种潜在治疗策略。
Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalizadon of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.