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）：糖尿病性肾病（DN）仍然是终末期肾衰竭（ESRD）的主要原因，需要开发更敏感的生物标志物和新的治疗靶标，以停止使用微阵列的进度。 RTN1A阴性与估计的肾小球过滤率（EGFR）相关的DN模型的鼠模型不包括DN的模型。降低的表达转化率相反，在体外降低了女霉素，高血糖和白蛋白诱导的ER应力和凋亡。在基于发现的输尿管实验模型中。 在此应用中，我们在DN的NT阶段提出了DN的进展确认是否可以开发RTN1A作为信任DN的潜在药物靶标。