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最常见的原因，在1型和2型糖尿病患者中都非常普遍。糖尿病患者的高血糖和肾内肾素-血管紧张素系统（RAS）的激活被认为在糖尿病肾病的发病机制中起关键作用。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不明确。转化生长因子-¿（TGF-¿）是高血糖反应中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（USF2）是高糖诱导的系膜细胞TGF-¿产生的重要转录因子。重要的是，USF2在糖尿病小鼠肾脏中的表达增加，并与肾小球系膜基质扩张相关。此外，在1型糖尿病小鼠模型中，USF2的过表达加速了糖尿病肾病的发展，支持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USF2在肾小球系膜细胞中促进肾素基因表达和血管紧张素II形成的新作用。USF2的这种作用与葡萄糖诱导的TGF-¿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。本提案的工作假设是USF2刺激肾脏RAS促进TGF-¿的产生，促进糖尿病肾病的发生。拟开展的研究将明确USF2在糖尿病肾病发展中的作用，重点关注作为机制靶点的肾小球系膜细胞肾素的调节。在目的1中，将确定USF2在正常或高葡萄糖条件下调节肾素基因表达和血管紧张素II产生的机制。在目标2中，将定义usf2介导的肾素表达和血管紧张素II产生在高糖诱导的TGF-¿水平和系膜细胞细胞外基质蛋白（ECM）表达中的作用。在目的3中，将确定usf2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，为糖尿病肾内RAS系统的激活机制提供了新的信息，并将导致新疗法的发展，以改善糖尿病的这一主要并发症。公共卫生相关性：糖尿病肾病是终末期肾衰竭最常见的原因，在1型和2型糖尿病患者中都非常普遍。这些研究将为糖尿病肾内肾素-血管紧张素系统的激活机制提供新的信息，并将导致新的治疗方法的发展，以改善糖尿病的这一主要并发症。

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.