Dual Oxidase 2 as a New Target for Treatment of Diabetic Nephropathy

项目概要/摘要 肾小球上皮细胞/足细胞损伤是糖尿病肾病的显著病理特征 （DN）。在足细胞中，高血糖引起裂膜蛋白、足突 细胞凋亡和细胞脱离，最终导致肾功能丧失的事件。高 葡萄糖浓度（HG）和氧化应激是肾小球损伤的潜在介质， 糖尿病我们有证据表明双氧化酶2（Duox 2）在肾小球细胞中表达， 有助于汞诱导的活性氧（ROS）的产生以及足细胞损伤。 此外，我们已经证明，从DuoxA-/-小鼠分离的肾小球受到保护， 高糖诱导过氧化氢生成。这一建议的核心假设是， Duox 2产生的活性氧在糖尿病肾小球病变和足细胞损伤中起关键作用 肾该提案的目标是利用体外和体内方法来建立 Duox 2在糖尿病环境中足细胞损伤中的重要性，并确定 调节Duox 2活性/表达。Duox激活剂（DuoxA）的作用，翻译机制， 和钙在Duox 2激活中的作用。对于体内研究，我们将利用先前的 从DuoxA功能受损的糖尿病和非糖尿病小鼠收集肾皮质。因为没有 可获得与足细胞内Duox酶表达和功能相关的数据， 建议应作为概念验证，以证明靶向Duox/DuoxA的效用 系统，以减少糖尿病介导的肾小球病变。有害作用的表征 Duox 2及其调节因子的鉴定将有助于设计新的治疗干预措施 并将有助于建立治疗DN的辅助疗法。这些研究将强调 开发肾脏中Duox 2表达和活性的调节剂作为治疗剂， 防止或逆转DN。此外，这项建议将加强研究和教育 基础设施在化身世界大学，介绍生物医学研究经验， 少数族裔学生人数不足，否则他们将缺乏这种机会。

Project Summary/Abstract Glomerular epithelial cell/podocyte injury is a prominent pathological feature of diabetic nephropathy (DN). In podocytes, hyperglycemia causes alteration of slit diaphragm proteins, foot process effacement, apoptosis and cell detachment, events that ultimately results in loss of renal function. High glucose concentrations (HG) and oxidative stress are potential mediators of glomerular injury in diabetes. We have evidence that Dual oxidase 2 (Duox2) is expressed in glomerular cells and contributes to HG-induced reactive oxygen species (ROS) generation as well as podocyte injury. Additionally, we have demonstrated that glomeruli isolated from DuoxA-/- mice were protected from high glucose-induced hydrogen peroxide generation. The central hypothesis of this proposal is that the ROS generated by Duox2 play a pivotal role in glomerular lesions and podocyte injury in the diabetic kidney. The goals of this proposal are to utilize in vitro and in vivo approaches to establish the importance of Duox2 in podocyte injury in the diabetic environment and identify the factors that are modulating Duox2 activity/expression. The role of Duox activators (DuoxA), translational mechanisms, and calcium in Duox2 activation will be explored. For the in vivo studies, we will utilize previously collected kidney cortices from diabetic and non-diabetic mice where DuoxA function is impaired. As no data related to Duox enzyme expression and function within podocytes are available, the experiments proposed should serve as proof of concept to demonstrate the utility of targeting the Duox/DuoxA system to reduce diabetes-mediated glomerular lesions. Characterization of the deleterious actions of Duox2 and identification of its regulators will contribute to the design of novel therapeutic interventions and will help establish adjunct therapy to treat DN. The studies will stress the relevance of the development of modulators of Duox2 expression and activity in the kidney as therapeutic agents to prevent or reverse DN. Furthermore, this proposal will enhance the research and educational infrastructure at the University of the Incarnate Word, introducing biomedical research experiences to underrepresented minority students who would otherwise lack such opportunities.