Role of RARRES1 in diabetic kidney disease

RARRES1 在糖尿病肾病中的作用

• 批准号: 10461883
• 负责人: John Cijiang He
• 金额: $ 44.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461883
• 关键词: Address; Adriamycin PFS; Alanine; Albuminuria; Amino Acids; Apoptosis; Apoptotic; Attenuated; Cell Cycle Arrest; Cell Death; Cell model; Cells; Cessation of life; Data; Data Set; Detection; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; Disease Progression; End stage renal failure; Endothelial Cells; Enzymes; Epithelial Cells; Event; Experimental Models; Extracellular Domain; Filtration; Focal Segmental Glomerulosclerosis; Future; Gene Expression; Genes; Glomerular Filtration Rate; Homeostasis; Human; In Vitro; Incidence; Induction of Apoptosis; Injury; Integral Membrane Protein; Kidney; Kidney Diseases; Knowledge; Maps; Matrix Metalloproteinases; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Mus; Nephrotic Syndrome; Oncogenic; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Persons; Plasma; Point Mutation; Prognostic Marker; Protein Kinase; Proteins; Publishing; Regulation; Renal glomerular disease; Reporting; Research Proposals; Retinoic Acid Receptor; Role; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; System; TNF gene; TP53 gene; Therapeutic; Translating; Tretinoin; Tubular formation; Tumor Suppressor Proteins; Type 2 diabetic; Urine; Work; base; biobank; cell injury; cohort; diabetic; glomerular endothelium; in vivo; kidney cell; knock-down; mRNA Expression; mouse model; mutant; novel; overexpression; paracrine; podocyte; response; risk variant; transcriptomics; type I diabetic; uptake; urinary

PROJECT SUMMARY Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) in the US, and podocyte injury is a key event in DKD and primary glomerular diseases. In vitro and in vivo studies with experimental mouse models demonstrated a protective role of retinoic acid (RA) against podocyte injury in glomerular diseases, but these findings had not been validated in human studies. Leveraging the glomerular transcriptomic datasets of human primary glomerular disease available from the Nephrotic Syndrome Study Network Consortium (NEPTUNE), we recently identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression was negatively correlated with estimated glomerular filtration rate (eGFR) decline and associated with worsened renal outcomes in patients with primary glomerular disease, suggesting that RARRES1 is a risk gene for human glomerular disease. Since RA signaling had been shown to be largely renoprotective against podocyte injury in experimental CKD models, these results suggested that RA signaling in vivo may in fact confer dichotomous cytoprotective (RARRES1-independent) and cytopathic (RARRES1- dependent) effects in the regulation of podocyte homeostasis. Indeed, our in vitro and in vivo findings show that increased podocyte RARRES1 expression leads to podocytopathy in mice, whereas decreased RARRES1 mitigates podocyte injury and disease progression in experimental mouse model of FSGS. Mechanistically, the cleavage of membrane-bound RARRES1 in its extracellular domain into a soluble form (sRARRES1) and its subsequent endocytic uptake is required for RARRES1-mediated podocyte apoptosis. These results indicate a critical role of RARRES1-mediated podocyte injury in glomerular disease, which were recently published in JCI [Chen et al. 2020, PMID: 32634130]. Expanding on these results, we further posit that RARRES1 is a key pathogenic inducer of podocyte loss and DKD progression. Since RARRES1 cleavage is critical for the podocyte apoptosis in vivo, a better understanding of RARRES1 cleavage mechanism can be translated therapeutically to attenuate podocyte loss in DKD, and ii) since sRARRES1 levels increase in the plasma and urine of DKD patients, plasma and urinary sRARRES1 may serve as a prognostic biomarker of DKD progression. Therefore, in this application we propose to 1) examine the mechanism of RARRES1 cleavage and its role in kidney cell injury in vitro; 2) Examine the contribution of RARRES1 in DKD pathogenesis in vivo; and 3) Examine whether the sRARRES1 detection can be utilized as a prognostic biomarker for future incidence or progression of DKD, leveraging two cohorts (ISMMS BioMe biobank and ACCORD). Moreover, this proposal will address the current knowledge gap on the dichotomous role of RA in podocyte homeostasis.

项目摘要 糖尿病肾脏疾病（DKD）是美国终末期肾脏疾病（ESRD）的最常见原因， 足细胞损伤是DKD和原发性肾小球疾病的关键事件。体外和体内研究 实验小鼠模型表明，视黄酸（RA）针对足细胞损伤的保护作用 肾小球疾病，但这些发现尚未在人类研究中得到验证。利用肾小球 人类原发性肾小球疾病的转录组数据集可从肾病综合征研究 网络财团（海王星），我们最近确定了视黄酸受体响应者蛋白1（Rarres1） 作为一个基因，其表达与估计的肾小球滤过率（EGFR）下降呈负相关 并且与原发性肾小球疾病患者的肾脏结局恶化有关，这表明 Rarres1是人肾小球疾病的风险基因。由于RA信号已被证明很大 在实验性CKD模型中，针对足细胞损伤的重新保护作用，这些结果表明RA信号在 实际上，体内可能会赋予二分法细胞保护（rarres1独立）和细胞病（Rarres1- 依赖性）对足细胞稳态调节的影响。确实，我们的体外和体内发现表明 足细胞rarres1表达增加导致小鼠的足细胞病，而rarres1降低 在FSG的实验小鼠模型中减轻足细胞损伤和疾病进展。机械上， 在其细胞外结构域中裂解膜结合的rarars1成一个可溶性形式（Srarres1）及其 RARRES1介导的足细胞凋亡需要随后的内吞摄取。这些结果表明 RARRES1介导的足细胞损伤在肾小球疾病中的关键作用，这些疾病最近在JCI中发表 [Chen等。 2020，PMID：32634130]。扩展这些结果，我们进一步认为Rarres1是关键 足细胞损失和DKD进展的致病诱导剂。由于rarres1裂解对于足细胞至关重要 在体内凋亡，可以更好地理解RARRES1切割机制 DKD中的足细胞损失，II）由于Srarres1水平在DKD患者的血浆和尿液中升高，所以 等离子体和尿液Srarres1可以作为DKD进展的预后生物标志物。因此，在此 应用我们建议1）检查rarres1裂解的机理及其在肾细胞损伤中的作用 体外2）检查rarres1在体内DKD发病机理中的贡献； 3）检查是否 Srarres1检测可以用作预后生物标志物，用于将来的DKD发病率或进展， 利用两个队列（ISMMS生物群生物库和协议）。此外，该提案将解决当前 关于RA在足细胞体内平衡中的二分法作用的知识差距。