Epithelial-mesenchymal transformation in diabetic nephropathy: Roles of oxidative stress and KLF transcription factors

糖尿病肾病的上皮间质转化：氧化应激和 KLF 转录因子的作用

• 批准号: nhmrc : 402443
• 负责人: A/Pr Xin-Ming Chen
• 金额: $ 37.18万
• 依托单位: The University of Sydney
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/epithelial-mesenchymal-transformation-transcription-factors/97471
• 关键词: Epithelial; mesenchymal; transformation; diabetic; nephropathy

Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction is possibly the greatest predictor of subsequent cardiovascular events (including heart attack, heart failure and stroke) a thorough understanding of the mechanism of progressive kidney failure in patients with diabetes is required so that effective therapeutic strategies may be developed. Preliminary data leading to the development of this proposal, has shown that normal kidney tubule cells 'transform' into fibroblastic-like cells, in a process known as epithelial-mesenchymal transformation (EMT), under the metabolic disturbances inherent in diabetes mellitus. These fibroblast-like cells are likely to be responsible for the progressive scarring in the kidney that is characteristic of irreversible renal failure. We have documented that a specific factor, transforming growth factor beta (TGFB1) is increased in kidney cells in the presence of diabetes mellitus, and our preliminary data suggests the action of TGB1 is regulated by the KLF-family of transcription factors. This project aims to determine whether metabolic conditions such as exposure to high glucose and oxidative stress induced by diabetes mellitus modifies the KLF factors within cells that then alter susceptibility to TGFB1 induced EMT. The specific pathways involved in EMT will be dissected using both cell culture models and animal models of diabetes mellitus. These pathways will be selectively interrupted to assess reversibility of the EMT process.

糖尿病是导致西方世界大多数肾脏疾病的原因。糖尿病肾病现在是美国卫生系统最大的单一成本。在澳大利亚，糖尿病肾病与肾小球肾炎一起占需要透析的肾衰竭病例的50%以上。随着糖尿病发病率的增加，目前的预测表明肾脏疾病患者人群的发病率可能会增加。由于肾功能不全的存在可能是随后心血管事件（包括心脏病发作、心力衰竭和中风）的最大预测因素，因此需要彻底了解糖尿病患者进行性肾衰竭的机制，以便制定有效的治疗策略。导致这一提议发展的初步数据已经表明，正常肾小管细胞在称为上皮-间充质转化（EMT）的过程中在糖尿病固有的代谢紊乱下“转化”成成纤维样细胞。这些成纤维细胞样细胞可能是造成肾脏中进行性瘢痕形成的原因，这是不可逆肾衰竭的特征。我们已经证明，一个特定的因子，转化生长因子β（TGFB 1）在糖尿病的存在下，在肾细胞中增加，我们的初步数据表明，TGB 1的行动是由KLF家族的转录因子调节。该项目旨在确定代谢条件，如暴露于糖尿病诱导的高葡萄糖和氧化应激，是否会改变细胞内的KLF因子，从而改变对TGFB 1诱导的EMT的易感性。将使用细胞培养模型和糖尿病动物模型来剖析EMT中涉及的具体途径。这些途径将被选择性地中断，以评估EMT过程的可逆性。