Role of RTN1A in the Progression of Diabetic Nephropathy

 描述(申请人提供)：糖尿病肾病(DN)仍然是美国终末期肾功能衰竭(ESRD)的主要原因，迫切需要开发更敏感的生物标志物和新的治疗目标来阻止糖尿病肾病的进展。利用进展性CKD小鼠模型的基因芯片图谱，我们发现，在包括糖尿病肾病模型在内的动物模型中，Rtn1a的肾脏表达与肾脏损伤的严重程度呈正相关。此外，肾小球滤过率(EGFR)与肾小球滤过率(EGFR)呈负相关。我们的初步数据表明，在体外，内质网相关蛋白RTN1a的表达增加诱导了内质网应激和肾细胞的凋亡，而其表达的降低反过来又减弱了衣霉素、高血糖和白蛋白诱导的内质网应激和细胞凋亡。在体内，Rtn1a的全局敲除可以减轻STZ诱导的糖尿病小鼠的蛋白尿、肾小球肥大和系膜扩张，以及在输尿管梗阻实验模型中的肾脏纤维化。基于这些发现，我们假设rtn1是一种潜在的肾脏疾病的新风险基因，并且它 通过内质网应激促进糖尿病肾病的进展。在这一应用中，我们提出了确定RTN1A在糖尿病不同阶段肾脏细胞特异性作用的目标，以及RTN1A在糖尿病条件下诱导ER应激和细胞凋亡的分子机制。本文建议的研究将证实RTN1A是否可能被开发为治疗糖尿病肾病的潜在药物靶点。

 DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) remains a leading cause of end-stage renal failure (ESRD) in the US, presenting an urgent need to develop more sensitive biomarkers and new targets of therapy to halt the progression of DN. Using a microarray profile of a murine model of progressive CKD, we found that the renal expression of Rtn1a positively correlated with the severity of renal injury in animal models, including a model of DN. In addition, expression of RTN1A negatively correlated with estimated glomerular filtration rate (eGFR) in DN patients. Our preliminary data demonstrates that the increased expression of RTN1A, an ER-associated protein, induces ER stress and apoptosis of renal cells and that its reduced expression conversely attenuates tunicamycin-, hyperglycemia-, and albumin-induced ER-stress and apoptosis in vitro. In vivo, a global knockdown of Rtn1a attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ- induced diabetic mice, as well as renal fibrosis in an experimental model of ureteral obstruction. Based on these findings, we posit that RTN1 is a potential novel risk gene for kidney disease and that it promotes the progression of DN through ER stress. In this application we put forward the aims to determine the renal cell- specific role of RTN1A in different stages of DN and the molecular mechanism by which RTN1A induces ER stress and apoptosis under diabetic conditions. The proposed studies herein will confirm whether RTN1A may be developed as a potential drug target to treat DN.