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: 10380165
• 负责人: John Cijiang He
• 金额: $ 45.15万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380165
• 关键词: ATP Synthesis Pathway; Acute Renal Failure with Renal Papillary Necrosis; Albumins; Albuminuria; Apoptosis; Apoptosis Regulation Gene; Apoptotic; Attenuated; Automobile Driving; Autophagocytosis; Cell Line; Cells; Chronic Kidney Failure; DNA copy number; Data; Data Set; Development; Diabetic Nephropathy; Diabetic mouse; Disease Progression; End stage renal failure; Endoplasmic Reticulum; Epithelial Cells; Event; Funding; Genes; Glucose; HK2 gene; Human; Immunoprecipitation; In Vitro; Incidence; Inflammasome; Inflammation; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Mass Spectrum Analysis; Measures; Mediating; Membrane; Membrane Potentials; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Mus; Oxidative Stress; Pathogenicity; Pathway interactions; Patients; Play; Prevalence; Preventive; Production; Proteins; RANK protein; Regimen; Regulation; Renal function; Reporting; Risk Factors; Role; Signal Transduction; Site; Streptozocin; Testing; Therapeutic; Therapeutic Effect; Tubular formation; Tunicamycin; attenuation; base; cell injury; db/db mouse; diabetic; diabetic patient; endoplasmic reticulum stress; glucose uptake; hexokinase; in vivo; inhibitor; kidney cell; kidney fibrosis; knock-down; mitochondrial dysfunction; mouse model; novel; overexpression; pleiotropism; screening; transcriptomics

Project Summary Diabetic kidney disease (DKD) remains as the leading cause of ESRD in USA and the treatment options are limited. Therefore, it is critical for us to identify contributing factors for the progression of DKD. By analyzing the transcriptomic datasets in mouse models with different rates of disease progression, we identified Reticulon-1 (Rtn1), a gene encoding an endoplasmic reticulum (ER)-associated protein, as a risk factor for progression of CKD. We found that RTN1A expression is markedly increased in the diseased kidney and inversely correlated with eGFR in human with DKD. In vitro, we showed that RTN1A mediates ER stress and apoptosis in renal tubular epithelial cells (RTEC). In vivo, we showed that a global knockdown of Rtn1a expression attenuated albuminuria and kidney injury in streptozotocin (STZ)-induced diabetic mice. During the last funding period, we further demonstrated that the induction of RTN1A expression in RTEC in the STZ-induced diabetic mice resulted in the decline of renal function and development of renal fibrosis, which are not typically observed in STZ-induced diabetic mice. Screening of RTN1A-interacting proteins surprisingly showed that the highly ranked proteins were mitochondrial proteins, such as hexokinase 1 (HK1), TOMM40, and SLC25A12. Consistent with this, a recent study also demonstrates a large amount of RTN1A in the ER-mitochondrial contact sites. ER-mitochondrial contact (EMC), or also referred as mitochondria-associated ER membranes (MAMs), have pleiotropic effects on a variety of intracellular events including mitochondrial damage, Ca2+ signaling, ER stress, apoptosis, and autophagy. However, the direct association of EMC with kidney disease has not been reported. Our preliminary data showed that overexpression of RTN1A in HK2 cells induced not only ER stress but also mitochondrial dysfunction. High glucose increased both ER stress and mitochondrial dysfunction in HK2 cells, which was further aggravated by RTN1A overexpression. In vivo, diabetic mice with RTN1A overexpression in RTEC had increased markers for both ER stress and mitochondrial dysfunction. These data suggest a critical role of RTN1A in mediating both ER stress and mitochondrial dysfunction likely through EMC. Also, we confirmed that RTN1A interacted with HK1 and induced the degradation of HK1 in RTEC and HK1 is a key regulator of apoptosis and inflammasome activation. Based on these data, we hypothesize that RTN1A-mediated EMC plays a critical role in inducing tubular cell injury and the progression of DKD. To test this, we propose to determine 1) the role of RTN1A in mediating EMC in RTEC injury in diabetic condition; 2) the mechanism of RTN1A-mediated EMC in RTEC injury in diabetic condition; and 3) the potential interventions to regulate EMC as a therapy for DKD.

项目总结