Role of mTOR in podocyte function and diabetic nephropathy in humans and mice
Role of mTOR in podocyte function and diabetic nephropathy in humans and mice
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DOI：
10.1172/jci44774
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Huber, Tobias B.
中科院分区：
文献类型：
--
作者：
Goedel, Markus;Hartleben, Bjoern;Huber, Tobias B.
慢性肾小球疾病，与肾衰竭和心血管疾病的发病率，是一个主要的健康问题。然而，人们对它们仍然知之甚少。在这里，我们报道了严格控制的mTOR活性对维持肾小球足细胞功能至关重要，而mTOR的失调促进肾小球疾病。小鼠足细胞中mTOR复合物1（mTORC 1）的基因缺失诱导蛋白尿和进行性肾小球硬化。此外，mTORC 1和mTORC 2从小鼠足细胞中同时缺失加重了肾小球病变，揭示了两种mTOR复合物对足细胞稳态的重要性。相比之下，mTOR活性增加伴随人类糖尿病肾病，其特征在于早期肾小球肥大和超滤。通过遗传性降低足细胞中mTORC1拷贝数来减少小鼠中mTORC1信号传导，可预防肾小球硬化，并显著改善糖尿病肾病中肾小球疾病的进展。这些结果证明了在足细胞稳态中需要紧密平衡的mTOR活性，并表明mTOR抑制可以保护足细胞并预防进行性糖尿病肾病。
Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.