Upstream Stimulatory Factor 2 regulation of renin in diabetic nephropathy

描述（由申请人提供）：糖尿病肾病是终末期肾衰竭的最常见原因，在1型和2型糖尿病患者中非常普遍。高血压和肾内肾素-血管紧张素系统（RAS）的激活在糖尿病肾病的发病机制中起重要作用。然而，RAS抑制剂或血管紧张素II作为糖尿病肾病介质的有效性机制尚未明确。转化生长因子-<$（TGF-<$）是高血糖导致肾纤维化的主要效应因子。初步数据表明，上游刺激因子（USF 2）是高糖诱导的系膜细胞TGF-β产生的重要转录因子。重要的是，USF 2表达在糖尿病小鼠的肾脏中增加，并且与肾小球系膜基质扩张相关。此外，USF 2的过表达加速了1型糖尿病小鼠模型中糖尿病肾病的发展，支持了该转录因子在糖尿病肾病发展中的作用。我们的初步研究描述了一种新的影响USF 2促进肾系膜细胞的肾素基因表达和血管紧张素II的形成。USF 2的这种作用与葡萄糖诱导的TGF-β产生的调节有关，这表明该途径可能有助于糖尿病肾病的发展。这项提议的工作假设是USF 2刺激肾脏RAS以促进TGF-β的产生和糖尿病肾病的发展。拟议的研究将确定USF 2在糖尿病肾病发展中的作用，重点是作为机制靶点的系膜细胞肾素的调节。在目标1中，将确定USF 2在正常或高糖条件下调节肾小球系膜细胞中的肾素基因表达和血管紧张素II产生的机制。在目标2中，将确定USF 2介导的肾素表达和血管紧张素II产生在高糖诱导的TGF-β水平和系膜细胞中细胞外基质蛋白（ECM）表达中的作用。在目的3中，将确定USF 2介导的肾RAS上调在体内糖尿病肾病发展中的作用。我们的方法利用体外和体内研究，提供新的信息的机制激活的肾内RAS系统在糖尿病，并将导致新的治疗方法的发展，以改善这一主要并发症的糖尿病。公共卫生相关性：糖尿病肾病是终末期肾衰竭的最常见原因，并且在1型和2型糖尿病患者中高度流行。拟议的研究将提供新的信息，激活的机制，肾内的肾素-血管紧张素系统在糖尿病，并将导致新的治疗方法的发展，以改善这一主要并发症的糖尿病。

DESCRIPTION (provided by applicant): 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. Public health relevance: Diabetic nephropathy is the most common cause of end-stage renal failure, and is highly prevalent in both type 1 and type 2 diabetics. The proposed studies will provide new information on the mechanisms of activation of the intrarenal renin-angiotensin system in diabetes, and will lead to the development of novel therapies to ameliorate this major complication of diabetes.