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

TSC-mTORC1 通路在糖尿病肾病足细胞损伤中的作用

• 批准号: 7740101
• 负责人: Ken Inoki
• 金额: $ 35.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740101
• 关键词: Albuminuria; Attention; Autophagocytosis; Cell physiology; Complex; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; End stage renal failure; Epithelial Cells; Foot Process; Genetic Transcription; Glomerular Capillary; Glucose; Goals; Growth; Growth Factor; Hyperglycemia; Hypertrophy; Injury; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Microalbuminuria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathogenesis; Pathway interactions; Patients; Play; Prevalence; Prevention; Proteins; Proteinuria; Raptors; Regulation; Resistance; Role; Scientist; Serum Proteins; Signal Pathway; Sirolimus; Site; Staging; Surface; TSC1 gene; Translations; diabetic; diabetic patient; glomerular basement membrane; glomerulosclerosis; human FRAP1 protein; in vivo; mTOR Inhibitor; mimetics; mouse model; nephrin; non-diabetic; novel; novel strategies; novel therapeutic intervention; podocyte; prevent; public health relevance; slit diaphragm; type I and type II diabetes

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.

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。其特征在于发展为肾小球硬化的主要肾小球病，最终导致终末期肾病（ESRD）。尽管临床医生和基础科学家都给予了相当大的关注，但糖尿病患者中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。近年来的研究表明足细胞损伤在糖尿病肾病的发生发展中起着重要作用。这些高度分化的肾小球上皮细胞和它们的足突组成了裂隔膜，一种排斥肾小球毛细血管表面上的血清蛋白的屏障。足细胞损伤可能产生微量白蛋白尿，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，足细胞损伤是否是DN的原因或后果也仍然不确定。TSC-mTORC 1通路是一种进化上保守的信号通路，调节生长和存活。该途径响应于营养物质，如葡萄糖和生长因子，并反过来控制广泛的细胞过程，如翻译，转录和自噬。我们已经证明mTORC 1通路的激活在糖尿病依赖性足细胞损伤中起着关键作用。我们的研究表明，DN小鼠模型中存在的所有病理学改变，包括足细胞形态学变化、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mTORC 1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mTORC 1的位点特异性激活起着关键作用。为了更详细地探讨这种可能性，我将重点了解糖尿病期间足细胞中TSC-mTORC 1通路的调节方式; mTORC 1依赖性足细胞损伤的分子机制;以及足细胞中mTORC 1的激活是否足以产生DN。我预计这些研究将揭示更多关于足细胞损伤的分子机制，并为开发治疗这种衰弱性疾病的新方法提供重要线索。公共卫生相关性：近年来的研究发现足细胞损伤在糖尿病肾病的发生发展中起着重要作用。本研究的目的是阐明mTOR通路作为糖尿病肾病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，还将为进一步研究探索治疗DN的新治疗方法奠定基础。