Role of RARRES1 in diabetic kidney disease
RARRES1 在糖尿病肾病中的作用
基本信息
- 批准号:10662465
- 负责人:
- 金额:$ 44.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Adriamycin PFSAlanineAlbuminuriaAmino AcidsApoptosisApoptoticAttenuatedCell Cycle ArrestCell DeathCell modelCellsCessation of lifeCytoprotectionDataData SetDetectionDiabetes MellitusDiabetic NephropathyDiabetic mouseDiseaseDisease ProgressionEnd stage renal failureEndothelial CellsEnzymesEpithelial CellsEventExperimental ModelsExtracellular DomainFiltrationFocal and Segmental GlomerulosclerosisFutureGene ExpressionGenesGlomerular Filtration RateHomeostasisHumanIn VitroIncidenceInduction of ApoptosisInjuryIntegral Membrane ProteinKidneyKidney DiseasesKnowledgeMapsMatrix MetalloproteinasesMediatingMembraneMessenger RNAModelingMolecularMusNephrotic SyndromeOncogenicOutcomePathogenesisPathogenicityPathway interactionsPatientsPeptide HydrolasesPersonsPhosphotransferasesPlasmaPoint MutationPrognostic MarkerProtein KinaseProteinsPublishingRegulationRenal glomerular diseaseReportingResearch ProposalsRetinoic Acid BindingRetinoic Acid ReceptorRoleSignal InductionSignal PathwaySignal TransductionSiteSite-Directed MutagenesisSystemTNF geneTP53 geneTherapeuticTranslatingTretinoinTubular formationTumor Suppressor ProteinsUrineWorkbiobankcell injurycohortdiabeticglomerular endotheliumin vivokidney cellknock-downmRNA Expressionmouse modelmutantnoveloverexpressionparacrinepodocyteresponserisk varianttranscriptomicsuptakeurinary
项目摘要
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.
项目总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hepatic and proximal tubule angiotensinogen play distinct roles in kidney dysfunction, glomerular and tubular injury, and fibrosis progression.
肝和近曲小管血管紧张素原在肾功能障碍、肾小球和肾小管损伤以及纤维化进展中发挥着独特的作用。
- DOI:10.1152/ajprenal.00029.2022
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Jang,Hee-Seong;Noh,MiRa;Plumb,Troy;Lee,Kyung;He,JohnCijiang;Ferrer,FernandoA;Padanilam,BabuJ
- 通讯作者:Padanilam,BabuJ
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John Cijiang He其他文献
Bisphenol A promotes hyperuricemia via activating xanthine oxidase
双酚A通过激活黄嘌呤氧化酶促进高尿酸血症
- DOI:
10.1096/fj.201700755r - 发表时间:
2017-10 - 期刊:
- 影响因子:0
- 作者:
Linqiang Ma;Jinbo Hu;Jiayu Li;Yi Yang;Linkun Zhang;Lingyun Zou;Rufei Gao;Yue Wang;Ting Luo;Xiaojiao Xiang;Hua Qing;Xiaoqiu Xiao;Chaodong Wu;Zhihong Wang;John Cijiang He;Qifu Li;Shumin Yang - 通讯作者:
Shumin Yang
An update: the role of Nephrin inside and outside the kidney
- DOI:
10.1007/s11427-015-4844-1 - 发表时间:
2015-04-29 - 期刊:
- 影响因子:9.500
- 作者:
XueZhu Li;John Cijiang He - 通讯作者:
John Cijiang He
A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury
新发现的C5a受体1在肾小管中对毒素诱导的急性肾损伤的保护作用
- DOI:
10.1016/j.ajpath.2024.10.003 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:3.600
- 作者:
Samuel Mon-Wei Yu;Emily King;Miguel Fribourg;Susan Hartzell;Liam Tsou;Logan Gee;Vivette D. D'Agati;Joshua M. Thurman;John Cijiang He;Paolo Cravedi - 通讯作者:
Paolo Cravedi
Bisphenol A promotes hyperuricemia via activating xanthine oxidase
- DOI:
doi: 10.1096/fj.201700755R - 发表时间:
- 期刊:
- 影响因子:
- 作者:
Linqiang Ma;Jinbo Hu;Jiayu Li;Yi Yang;Linkun Zhang;Lingyun Zou;Rufei Gao;Chuan Peng;Yue Wang;Ting Luo;Xiaojiao Xiang;Hua Qing;Xiaoqiu Xiao;Chaodong Wu;Zhihong Wang;John Cijiang He;Qifu Li;Shumin Yang - 通讯作者:
Shumin Yang
RETRACTED ARTICLE: LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma
撤回文章:长链非编码 RNA HOTAIR 通过抑制肾细胞癌中的 miR-217 调节 HIF-1α/AXL 信号通路
- DOI:
10.1038/cddis.2017.181 - 发表时间:
2017-05-11 - 期刊:
- 影响因子:9.600
- 作者:
Quan Hong;Ou Li;Wei Zheng;Wen-zhen Xiao;Lu Zhang;Di Wu;Guang-yan Cai;John Cijiang He;Xiang-mei Chen - 通讯作者:
Xiang-mei Chen
John Cijiang He的其他文献
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{{ truncateString('John Cijiang He', 18)}}的其他基金
The role of Vpr-mediated cell cycle dysregulation in HIV-associated kidney disease
Vpr 介导的细胞周期失调在 HIV 相关肾病中的作用
- 批准号:
10678878 - 财政年份:2022
- 资助金额:
$ 44.7万 - 项目类别:
The role of Vpr-mediated cell cycle dysregulation in HIV-associated kidney disease
Vpr 介导的细胞周期失调在 HIV 相关肾病中的作用
- 批准号:
10527702 - 财政年份:2022
- 资助金额:
$ 44.7万 - 项目类别:
Role of RARRES1 in diabetic kidney disease
RARRES1 在糖尿病肾病中的作用
- 批准号:
10278234 - 财政年份:2021
- 资助金额:
$ 44.7万 - 项目类别:
Elucidating the Molecular Mechanisms that Mediate DKD Progression in Patients Living with HIV
阐明介导 HIV 感染者 DKD 进展的分子机制
- 批准号:
10364063 - 财政年份:2021
- 资助金额:
$ 44.7万 - 项目类别:
Role of RARRES1 in diabetic kidney disease
RARRES1 在糖尿病肾病中的作用
- 批准号:
10461883 - 财政年份:2021
- 资助金额:
$ 44.7万 - 项目类别:
Elucidating the Molecular Mechanisms that Mediate DKD Progression in Patients Living with HIV
阐明介导 HIV 感染者 DKD 进展的分子机制
- 批准号:
10531888 - 财政年份:2021
- 资助金额:
$ 44.7万 - 项目类别:
PP2A as a drug target for diabetic kidney disease
PP2A作为糖尿病肾病的药物靶点
- 批准号:
10399582 - 财政年份:2020
- 资助金额:
$ 44.7万 - 项目类别:
PP2A as a drug target for diabetic kidney disease
PP2A作为糖尿病肾病的药物靶点
- 批准号:
10627834 - 财政年份:2020
- 资助金额:
$ 44.7万 - 项目类别:
Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies
增殖性肾小球病中足细胞-壁上皮细胞串扰的介导机制
- 批准号:
10434116 - 财政年份:2020
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Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies
增殖性肾小球病中足细胞-壁上皮细胞串扰的介导机制
- 批准号:
10119964 - 财政年份:2020
- 资助金额:
$ 44.7万 - 项目类别:
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