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，并且在两种类型中都非常普遍 1型和2型糖尿病患者。高血压与肾内肾素-血管紧张素系统（RAS）的激活 糖尿病在糖尿病肾病的发病机制中起着关键作用。但 RAS抑制剂的有效性机制，或血管紧张素II作为糖尿病的介导剂， 肾病没有很好的定义。转化生长因子-<$（TGF-<$）是导致肾脏疾病的主要效应因子， 纤维化反应高血糖症。初步数据表明，上游刺激因子（USF2） 是高糖诱导系膜细胞产生TGF-β的重要转录因子。重要的是， 糖尿病小鼠肾脏USF2表达增加，与肾小球系膜细胞凋亡相关。 矩阵展开此外，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，支持这种转录因子在糖尿病肾病中的作用。 糖尿病肾病的治疗我们的初步研究描述了USF 2促进 肾小球系膜细胞中肾素基因表达和血管紧张素II形成。USF2的这种影响与以下因素有关： 葡萄糖诱导的TGF-β产生的调节，表明这一途径可能有助于 糖尿病肾病的治疗这项建议的工作假设是，USF2刺激了 肾RAS促进TGF-β的产生和糖尿病肾病的发展。拟议 研究将确定USF2在糖尿病肾病发展中的作用，重点是调节 系膜细胞肾素作为机制靶点。目的1：探讨USF2对肾素基因的调控机制 在正常或高糖条件下，系膜细胞中血管紧张素II的表达和血管紧张素II的产生将被 测定在目的2中，USF2介导的肾素表达和血管紧张素II的产生在高血压中的作用。 葡萄糖诱导的TGF-β水平和系膜细胞中的细胞外基质蛋白（ECM）表达将被 定义了在目的3中，研究USF2介导的肾RAS上调在糖尿病发展中的作用。 将测定体内肾病。我们的方法利用体外和体内研究来提供新的 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.