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: 8527765
• 负责人: Ken Inoki
• 金额: $ 30.27万
• 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/8527765
• 关键词: Albuminuria; Attention; Autophagocytosis; Cell physiology; Complex; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; End stage renal failure; Epithelial Cells; Foot Process; Genetic Transcription; Glomerular Capillary; Glucose; Goals; Growth; Growth Factor; Health; 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; 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）：糖尿病性肾病（DN）是1型和2型糖尿病患者中最致命的并发症之一。它的特征是发展为肾小球硬化的主要肾小球病，最终导致终末期肾脏疾病（ESRD）。尽管临床医生和基础科学家都非常关注，但糖尿病患者ESRD的普遍性仍在显着增加。因此，了解DN的发病机理对于开发新方法的预防和治疗至关重要。最近的研究表明，足细胞的伤害在糖尿病性肾病的发展中起着关键作用。这些高度分化的肾小球上皮细胞及其脚部过程包括缝隙膜片，这是在肾小球毛细血管表面排除血清蛋白的障碍。足细胞损伤可能会产生微藻尿症，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的原因还是导致DN的结果。 TSC-MTORC1途径是一种调节生长和存活的进化保守的信号通路。该途径对诸如葡萄糖和生长因子之类的营养有反应，进而控制了各种细胞过程，例如翻译，转录和自噬。我们已经表明，MTORC1途径的激活在依赖糖尿病的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变化，包括足细胞形态学变化，肾小球基底膜（GBM）增厚，蛋白尿，肾小球肥大和肾小球膨胀，可以通过用雷帕素（Rapamycin）处理（一种特定的mtor抑制剂）来预防。此外，在非糖尿病小鼠概括的足细胞损伤和雷帕霉素敏感方式的其他特征中，足细胞特异性的MTORC1激活。这些观察结果表明，在DN发育过程中，MTORC1特定于位点特异性激活的作用至关重要。为了更详细地探讨这种可能性，我将重点介绍如何在糖尿病期间如何调节TSC-MTORC1途径。 MTORC1依赖性足细胞损伤的分子机制；以及足细胞中MTORC1的激活是否足以产生DN。我预计这些研究将大大揭示DN中足细胞损伤的分子机制，并为开发新方法治疗这种衰弱的疾病提供了重要的线索。公共卫生相关性：最近的调查表明，足细胞的伤害在糖尿病性肾病（DN）的发展中起着至关重要的作用。该提案的目的是阐明MTOR途径作为DN中足细胞损伤的分子机制的作用。该项目的完成不仅会揭示出一种新型的足细胞损伤分子机制，而且还为探索DN治疗的新的治疗方法奠定了基础。