Role of RTN1A in the Progression of Diabetic Nephropathy

RTN1A 在糖尿病肾病进展中的作用

• 批准号: 9126016
• 负责人: John Cijiang He
• 金额: $ 38.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-18 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126016
• 关键词: AIDS-Associated Nephropathy; Advanced Glycosylation End Products; Affect; Albumins; Animal Model; Apoptosis; Attenuated; Automobile Driving; Binding; Biological Markers; C-terminal; Cells; Chronic Kidney Failure; Collaborations; Data; Data Set; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; Disease Progression; Doxycycline; Drug Targeting; End stage renal failure; Endoplasmic Reticulum; Experimental Models; Fibrosis; GRP78 gene; Gene Chips; Gene Expression; Genes; Genetic study; Glomerular Filtration Rate; Glucose; Growth; HK2 gene; Heat shock proteins; Human; Hyperglycemia; Hypertrophy; In Vitro; Incidence; Injection of therapeutic agent; Injury; Interleukin-6; Kidney; Kidney Diseases; Kidney Failure; Length; Maps; Measures; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Mus; N-terminal; Nerve Regeneration; Neurodegenerative Disorders; Patients; Prevalence; Preventive; Protein Family; Protein Isoforms; Proteins; Proteinuria; RTN1 gene; RTN4 gene; Reactive Oxygen Species; Regimen; Regulation; Role; Severities; Shapes; Staging; Streptozocin; Therapeutic; Therapeutic Effect; Transforming Growth Factor beta; Transgenic Mice; Tunicamycin; Ureteral obstruction; Withdrawal; attenuation; base; biological adaptation to stress; cell type; cytokine; db/db mouse; diabetic; diabetic patient; endoplasmic reticulum stress; glomerulosclerosis; in vivo; kidney cell; knock-down; member; mouse model; mutant; new therapeutic target; novel; overexpression; promoter; protein transport; public health relevance; research study; risk variant; stress protein; transcription factor; type I diabetic

 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.

 描述（由申请人提供）：糖尿病肾病（DN）仍然是美国终末期肾衰竭（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靶点，以阻止DN的进展。使用进行性CKD小鼠模型的微阵列图谱，我们发现Rtn1a的肾脏表达与动物模型（包括DN模型）中肾损伤的严重程度呈正相关。此外，在DN患者中，RTN1A的表达与估计的肾小球滤过率（eGFR）呈负相关。我们的初步数据表明，RTN1A，ER相关蛋白的表达增加，诱导ER应激和肾细胞凋亡，其表达减少，反过来减弱衣霉素，高血糖症，白蛋白诱导的ER应激和细胞凋亡在体外。在体内，Rtn1a的整体敲低减轻了STZ诱导的糖尿病小鼠的蛋白尿、肾小球肥大和系膜扩张，以及输尿管梗阻实验模型中的肾纤维化。基于这些发现，我们认为RTN1是一个潜在的肾脏疾病的新的风险基因，它可能是一个潜在的肾脏疾病的新的风险基因。 通过ER应激促进DN的进展。在本申请中，我们提出了确定RTN1A在DN的不同阶段中的肾细胞特异性作用以及RTN1A在糖尿病条件下诱导ER应激和细胞凋亡的分子机制的目的。本文提出的研究将确认RTN1A是否可以开发为治疗DN的潜在药物靶点。