AGE signaling in diabetic renal disease

糖尿病肾病中的 AGE 信号传导

• 批准号: 6646409
• 负责人: DAZHONG XU
• 金额: $ 4.62万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646409
• 关键词: SDS polyacrylamide gel electrophoresis; androstane compound; biological signal transduction; cell line; collagen; diabetic nephropathy; fibronectins; glycation; guanine nucleotide binding protein; immunoprecipitation; kidney cell; kidney hyperplasia; kidney hypertrophy; mitogen activated protein kinase; northern blottings; nucleic acid purification; pathologic process; phosphatidylinositol 3 kinase; phosphorylation; postdoctoral investigator; protein protein interaction; receptor; receptor expression; transfection; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): Nephropathy is one of the major complications of both type 1 and type 2 diabetes mellitus. Thus approximately 40% of individuals with diabetes will develop kidney disease, and renal failure accounts for a significant proportion of the mortality attributable to diabetes. The progression to diabetic kidney disease is a complex and poorly understood process. Elevated plasma glucose triggers the secretion of transforming growth factor-beta (TGF-Beta) which, in turn, stimulates the pathologically excessive deposition of extracellular matrix-a process mediated by glomerular mesangial cells. Elevated blood glucose also stimulates mesangial cell hyperplasia and hypertrophy. These processes eventually culminate in renal failure. While a direct signaling role for glucose has been proposed, glucose itself is a weak mesangial cell agonist. Advanced glycation endproducts (AGEs), formed by the nonenzymatic glycation of proteins and lipids, are present in excess in diabetes and are thought to be important early in the development of diabetic renal disease. AGEs exert their effects by interacting with the receptor for advanced glycation endproducts (RAGE). RAGE expression is elevated in diabetes. Blockade of RAGE has been shown to suppress vascular hyperpermeabiity and accelerated atherosclerosis in diabetic rats. These results, suggest that AGEs/RAGE play a central role in triggering the early pathophysiologic changes associated with diabetic nephropathy. Accordingly, investigating RAGE intracellular signaling mechanisms and cellular effects is important to furthering our understanding of diabetic renal disease. We propose two broad areas of study: dissection of the signaling pathways coupling mesangial cell RAGE to ERK and PI-3-kinase and identification of signaling elements recruited by RAGE that are important to pathophysiologic changes of mesangial cells associated with diabetes.

描述（由申请人提供）：肾病是1型和2型糖尿病的主要并发症之一。因此，大约40％的糖尿病患者会患上肾脏疾病，肾衰竭占可归因于糖尿病的死亡率的很大比例。糖尿病性肾脏疾病的进展是一个复杂且知之甚少的过程。升高的血浆葡萄糖触发了转化生长因子-Beta（TGF-β）的分泌，这反过来刺激了肾小球膜细胞介导的细胞外基质-A过程的病理过度沉积。升高的血糖还刺激了膜细胞增生和肥大。这些过程最终导致肾衰竭。虽然已经提出了葡萄糖的直接信号传导作用，但葡萄糖本身是一种弱的膜细胞激动剂。由蛋白质和脂质的非酶糖基化形成的晚期糖基化最终产物（年龄）在糖尿病中过量存在，被认为在糖尿病肾脏疾病的早期很重要。年龄通过与高级糖基化最终产物（RAGE）的受体相互作用来发挥其作用。糖尿病中的愤怒表达升高。爆发的封锁已被证明可抑制糖尿病大鼠的血管性高温性和加速动脉粥样硬化。这些结果表明，年龄/愤怒在触发与糖尿病肾病相关的早期病理生理变化方面起着核心作用。因此，研究愤怒的细胞内信号传导机制和细胞效应对于进一步了解我们对糖尿病肾脏疾病的理解很重要。我们提出了两个广泛的研究领域：解剖偶联的膜细胞愤怒与ERK和PI-3-激酶的解剖，以及对与糖尿病相关的肾小球生理学变化重要的愤怒募集的信号传导元件的鉴定。