Upstream Stimulatory Factor 2 regulation of renin in diabetic nephropathy

糖尿病肾病是终末期肾功能衰竭最常见的原因，在这两种类型中都非常普遍。 1型和2型糖尿病患者。高血糖与肾素-血管紧张素系统激活 糖尿病被认为在糖尿病肾病的发病机制中起关键作用。然而， RAS或血管紧张素II抑制剂作为糖尿病介体的作用机制 肾病的定义不是很清楚。转化生长因子是导致肾脏病变的主要效应因子。 高血糖所致的纤维化。初步数据显示，上游刺激因子(USF2) 是高糖诱导系膜细胞产生转化生长因子β的重要转录因子。重要的是 USF2在糖尿病小鼠肾脏中的表达增加，并与肾小球系膜相关 矩阵扩展。此外，USF2的过度表达加速了糖尿病的发展 在1型糖尿病小鼠模型中的肾病，支持该转录因子在 糖尿病肾病的发展。我们的初步研究描述了一种新的USF2促进作用 肾小球系膜细胞肾素基因表达与血管紧张素II的形成USF2的这种效应与 葡萄糖诱导的转化生长因子-β的产生调节，提示这一途径可能有助于 糖尿病肾病的发展。这一提议的工作假设是，USF2刺激 肾RAS促进转化生长因子-β的产生，促进糖尿病肾病的发生发展。建议数 研究将确定USF2在糖尿病肾病发生发展中的作用，重点是调节 以肾小球系膜细胞肾素为机制靶点。在目标1中，USF2调节肾素基因的机制 在正常或高糖条件下，系膜细胞的表达和血管紧张素II的产生 下定决心。在目标2中，USF2介导的肾素表达和血管紧张素II产生在高血压病患者中的作用 葡萄糖诱导系膜细胞转化生长因子β水平和细胞外基质蛋白(ECM)表达 已定义。在目标3中，USF2介导的肾脏RAS上调在糖尿病发生发展中的作用 活体肾病将被确定。我们的方法利用体外和体内研究来提供新的 关于糖尿病肾内RAS系统激活机制的信息，并将导致 开发新的治疗方法来改善糖尿病的这一主要并发症。

Diabetic nephropathy is the most common cause of end-stage renal failure, and is highly prevalent in both type 1 and type 2 diabetics. Hyperglycemia and the activation of the intrarenal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of diabetic nephropathy. However, the mechanisms for the effectiveness of inhibitors of the RAS, or for angiotensin II as a mediator of diabetic nephropathy are not well defined. Transforming growth factor -¿ (TGF-¿) is a major effector leading to renal fibrosis in response to hyperglycemia. Preliminary data demonstrate that Upstream Stimulatory Factor (USF2) is an important transcription factor in high glucose-induced TGF-¿ production in mesangial cells. Importantly, USF2 expression is increased in the kidneys of diabetic mice and correlates with the glomerular mesangial matrix expansion. Furthermore, over-expression of USF2 accelerates the development of diabetic nephropathy in a type 1 diabetic mouse model, supporting the role of this transcription factor in the development of diabetic nephropathy. Our preliminary studies describe a novel effect of USF2 to promote renin gene expression and angiotensin II formation in mesangial cells. This effect of USF2 was linked to glucose-induced regulation of TGF-¿ production, suggesting that this pathway may contribute to the development of diabetic nephropathy. The working hypothesis of this proposal is that USF2 stimulates the renal RAS to promote production of TGF-¿ and the development of diabetic nephropathy. The proposed studies will define the role of USF2 in the development of diabetic nephropathy focusing on regulation of mesangial cell renin as the mechanistic target. In aim 1, the mechanisms by which USF2 regulates renin gene expression and angiotensin II production in mesangial cells under normal or high glucose conditions will be determined. In aim 2, the role of USF2-mediated renin expression and angiotensin II production in high glucose induced TGF-¿ levels and extracellular matrix protein (ECM) expression in mesangial cells will be defined. In aim 3, the role of USF2-mediated up-regulation of the renal RAS in the development of diabetic nephropathy in vivo will be determined. Our approach utilizes both in vitro and in vivo studies to provide new information on the mechanisms of activation of the intrarenal RAS system in diabetes, and will lead to the development of novel therapies to ameliorate this major complication of diabetes.