Renal Fibrosis in Diabetes

描述（由申请人提供）： 肾小管间质纤维化是包括糖尿病肾病在内的进行性肾病的一个突出病理特征。在糖尿病肾病和其他进行性肾脏疾病中，肾小管上皮细胞获得间充质细胞特征并积累基质蛋白，最终导致纤维化。糖尿病肾纤维化的两种潜在介质是高葡萄糖浓度和转化生长因子β。我们有证据表明，葡萄糖和TGF-β抑制能量传感器AMPK，这可能导致细胞获得间充质细胞特征并积累基质蛋白。本申请中提出的工作将利用体外和体内方法来确定AMPK是否确实是调节剂 并鉴定可能是AMPK效应物的下游信号转导通路。药理学和遗传学方法将用于在体外培养的肾小管上皮细胞和体内激活或抑制AMPK。对于体内研究，我们将在近端肾小管细胞中特异性地缺失AMPK的小鼠。此外，患有1型糖尿病的OVE 26小鼠将用于研究AMPK和下游信号通路（包括tuberin和mTOR）的作用。该建议的中心假设是AMPK通过翻译或转录途径调节糖尿病肾小管上皮细胞的基质蛋白积累和间质特征。这些研究将有助于建立除了代谢控制之外的辅助治疗来治疗糖尿病并发症。

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis is a prominent pathological feature of progressive renal disease including diabetic nephropathy. In diabetic nephropathy and other progressive renal diseases, tubular epithelial cells acquire mesenchymal cell characteristics and accumulate matrix proteins that eventuate in fibrosis. Two potential mediators of renal fibrosis in diabetes are high glucose concentrations and transforming growth factor-beta. We have evidence that glucose and TGF-beta inactivate the energy sensor AMPK and that this may result in the cells acquiring mesenchymal cell characteristics and accumulating matrix proteins. The work proposed in this application will utilize in vitro and in vivo approaches to establish if AMPK is indeed a modulator of renal fibrosis and identify downstream signal transduction pathway(s) that may be the effectors of AMPK. Pharmacological and genetic approaches will be used to activate or inhibit AMPK in vitro in cultured tubular epithelial cells and in vivo. For the in vivo studies, we will utlize mice deficient in AMPK specifically in proximal tubular cells. In addition, OVE26 mice with type 1 diabetes will be used to investigate the role of AMPK and downstream signaling pathways including tuberin and mTOR. The central hypothesis of this proposal is that AMPK regulates matrix protein accumulation and mesencymal characteristics of tubular epithelium in diabetes through translational or transcriptional pathways. The studies will help establish adjunct therapy in addition to metabolic control to treat the complications of diabetes.