Role of RARRES1 in diabetic kidney disease

RARRES1 在糖尿病肾病中的作用

• 批准号: 10278234
• 负责人: John Cijiang He
• 金额: $ 44.76万
• 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/10278234
• 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; 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 糖尿病肾病（DKD）是美国终末期肾病（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， 实验小鼠模型证实了维甲酸（RA）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学数据集，可从肾病综合征研究中获得 网络联盟（NEPTUNE），我们最近确定了视黄酸受体应答蛋白1（RARRES 1） 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， 并与原发性肾小球疾病患者的肾脏结局恶化相关，表明 RARRES 1是人类肾小球疾病的危险基因。由于RA信号在很大程度上被证明是 在实验性CKD模型中，RA对足细胞损伤具有肾保护作用，这些结果表明， 事实上，在体内可以赋予二分的细胞保护性（RARRES 1-非依赖性）和细胞病变性（RARRES 1-依赖性）。 依赖性）在足细胞稳态调节中的作用。事实上，我们的体外和体内研究结果表明， 足细胞RARRES 1表达增加导致小鼠足细胞病，而RARRES 1表达减少导致小鼠足细胞病。 减轻FSGS实验小鼠模型中的足细胞损伤和疾病进展。机械地， 将其细胞外结构域中的膜结合RARRES 1切割成可溶性形式（sRARRES 1）及其 随后的内吞摄取是RARRES 1介导的足细胞凋亡所必需的。这些结果表明 RARRES 1介导的足细胞损伤在肾小球疾病中的关键作用，最近发表在JCI上 [Chen等人2020，PMID：32634130]。在这些结果的基础上，我们进一步证明RARRES 1是一个关键因素， 足细胞损失和DKD进展的致病诱导物。由于RARRES 1切割对于足细胞至关重要， 在体内细胞凋亡中，对RARRES 1切割机制的更好理解可以在治疗上转化为 减轻DKD中的足细胞损失，和ii）由于DKD患者的血浆和尿液中sRARRES 1水平增加， 血浆和尿sRARRES 1可作为DKD进展的预后生物标志物。所以在这 我们提出的应用1）检查RARRES 1切割的机制及其在肾细胞损伤中的作用， 体外; 2）检查RARRES 1在体内DKD发病机制中的作用;和3）检查RARRES 1是否在DKD发病机制中起作用。 sRARRES 1检测可用作DKD未来发病率或进展的预后生物标志物， 利用两个队列（ISMMS BioMe生物库和雅阁）。此外，该提案将解决目前的 关于RA在足细胞稳态中的二分作用的知识缺口。