Role of TSC-mTORC1 pathway for podocyte injury in diabetic nephropathy

描述（由申请人提供）：糖尿病肾病（DN）是1型和2型糖尿病患者最致命的并发症之一。它的特点是发展为肾小球硬化的主要肾小球病变，最终导致终末期肾病（ESRD）。尽管临床医生和基础科学家都相当重视，糖尿病患者中ESRD的患病率正在急剧增加。因此，了解DN的发病机制对于开发新的预防和治疗方法至关重要。最近的研究表明足细胞损伤在糖尿病肾病的发展中起关键作用。这些高度分化的肾小球上皮细胞及其足突组成狭缝隔膜，这是肾小球毛细血管表面排斥血清蛋白的屏障。足细胞损伤可产生微量蛋白尿，这是DN的早期特征。糖尿病引起足细胞损伤的分子机制尚不清楚。此外，足细胞损伤是DN的原因还是结果也仍然不确定。TSC-mTORC1通路是一个进化保守的信号通路，调节生长和生存。这条通路对葡萄糖和生长因子等营养物质作出反应，并反过来控制一系列细胞过程，如翻译、转录和自噬。我们已经证明mTORC1通路的激活在糖尿病依赖性足细胞损伤中起关键作用。我们的研究表明，在小鼠DN模型中存在的所有病理改变，包括足细胞形态学改变、肾小球基底膜（GBM）增厚、蛋白尿、肾小球肥大和系膜扩张，都可以通过雷帕霉素（一种特异性mTOR抑制剂）治疗来预防。此外，在非糖尿病小鼠中，足细胞特异性mTORC1激活以雷帕霉素敏感的方式再现了足细胞损伤和DN的其他特征。这些观察结果表明，在DN的发展过程中，足细胞中mTORC1的位点特异性激活起着关键作用。为了更详细地探索这种可能性，我将重点了解糖尿病足细胞中TSC-mTORC1通路是如何调节的；mtorc1依赖性足细胞损伤的分子机制；足细胞中mTORC1的激活是否足以产生DN。我预计这些研究将揭示DN中足细胞损伤的分子机制，并为开发治疗这种使人衰弱的疾病的新方法提供重要线索。公共卫生相关性：最近的研究表明足细胞损伤在糖尿病肾病（DN）的发展中起关键作用。本文的目的是阐明mTOR通路作为DN足细胞损伤的分子机制的作用。该项目的完成不仅将揭示足细胞损伤的新分子机制，而且为进一步研究探索DN的新治疗方法奠定了基础。

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is among the most lethal complications that occur in patients with both type 1 and type 2 diabetes. It is characterized as a major glomerulopathy that develops to glomerulosclerosis, leading ultimately to end-stage renal disease (ESRD). Despite considerable attention from both clinicians and basic scientists, the prevalence of ESRD in diabetic patients is increasing dramatically. Thus, understanding the pathogenesis of DN is crucial to developing new approaches for its prevention and treatment. Recent investigations have revealed that injuries to podocytes play a critical role in the development of diabetic nephropathy. These highly differentiated glomerular epithelial cells and their foot processes comprise the slit diaphragm, a barrier for repelling serum proteins on the surface of glomerular capillaries. Podocyte injury may produce micro-albuminuria, an early feature of DN. The molecular mechanisms by which diabetes causes podocyte injury remain unclear. Furthermore, whether podocyte injury is a cause or a consequence of DN also continues to be uncertain. The TSC-mTORC1 pathway is an evolutionarily conserved signaling pathway that regulates growth and survival. This pathway responds to nutrients such as glucose and growth factors, and in turn controls a wide array of cellular processes such as translation, transcription, and autophagy. We have shown that activation of the mTORC1 pathway plays a critical role in diabetes-dependent podocyte injury. Our studies indicate that all pathological alterations present in a mouse model of DN, including podocyte morphological changes, glomerular basement membrane (GBM) thickening, proteinuria, glomerular hypertrophy, and mesangial expansion, can be prevented by treatment with rapamycin, a specific mTOR inhibitor. Moreover, podocyte-specific mTORC1 activation in a non-diabetic mouse recapitulated podocyte injury and other features of DN in a rapamycin-sensitive manner. These observations indicate a critical role for the site-specific activation of mTORC1 in podocytes during the development of DN. To explore this possibility in greater detail, I will focus on understanding how the TSC-mTORC1 pathway is regulated in podocytes during diabetes; the molecular mechanisms underlying mTORC1-dependent podocyte injury; and whether activation of mTORC1 in podocytes is sufficient to produce DN. I anticipate that these studies will reveal much about the molecular mechanisms underlying podocyte injury in DN, and provide important clues for developing new approaches to the treatment of this debilitating disease. PUBLIC HEALTH RELEVANCE: Recent investigations have revealed that injuries to podocytes play a critical role in the development of diabetic nephropathy (DN). The goal of this proposal is to elucidate the role of mTOR pathway as a molecular mechanism underlying podocyte injury in DN. Completion of this project will not only reveal a novel molecular mechanism for podocyte injury but also set the stage for additional studies to explore new therapeutic approaches to the treatment of DN.