PP2A as a drug target for diabetic kidney disease

PP2A作为糖尿病肾病的药物靶点

基本信息

项目摘要

Title: Role of PP2A in podocyte biology and diabetic kidney disease SUMMARY Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease with limited treatment options. Arctigenin (ATG) is a major component derived from the extracts of Fructus Arctii, a traditional Chinese herbal remedy that has shown to confer renoprotection and to reduce proteinuria in patients with DKD. Our preliminary data show that ATG administration alone is sufficient to attenuate proteinuria and podocyte injury in mouse models of type 1 and type 2 diabetes. Transcriptomic analysis of isolated glomeruli from the diabetic and control mice showed that the major pathways affected by ATG treatment were of cell adhesion and inflammation. ATG improved cell adhesion and inhibited migration in cultured human podocytes. By combining the Drug Affinity Responsive Target Stability (DARTS) technique with Mass Spectrometry analysis we identified protein phosphatase 2A (PP2A) as a top ATG-bound protein in cultured renal cells, and this was further confirmed by western blot, computational docking, and surface plasmon resonance assay. In addition, ATG enhanced the activity of PP2A in cultured podocytes and in diabetic glomeruli, resulting in dephosphorylation of p65 NF-κB. Studying the PP2A interacting proteins in podocytes by Mass Spectrometry identified Drebrin-1 (DBN1) as a F- actin interacting protein. Dephosphorylation of DBN1 at T335 by PP2A in podocytes resulted in increased cell adhesion and decreased migration. Importantly, podocyte-specific deletion of Pp2a in mice led to aggravated diabetes-induced podocyte and glomerular injury and the loss of efficacy in ATG-mediated renoprotection. In addition, we found that PPP2R2B, a regulatory subunit of PP2A, expresses uniquely in podocytes in human glomeruli. Its expression is downregulated in the glomeruli of human DKD. In human podocytes, the knockdown of PPP2R2B reduced PP2A activity and expression of PPP2R2B is suppressed by high glucose. Phenome Wide Association Scan identified several missense variants in the human PPP2R2B gene which were associated with either worse or better renal outcomes. These data support a critical role of PP2A in human kidney disease. Based on these observations, we hypothesized that PP2A plays a key role in podocyte biology and pathogenesis of DKD. To test our hypothesis, we will determine the regulation and function of PPP2R2B in podocyte. We will also study the role of PPP2R2B in the regulation of PP2A activity, subcellular localization, and podocyte function in vitro under diabetic conditions and determine whether induction of PPP2R2B or its diseased variant expression in podocytes affects podocyte injury and DKD progression in diabetic mice. We will also determine the downstream signaling of PP2A in podocytes by focusing on the role of DBN1. We will study how PP2A affects podocyte function through regulating DBN1 phosphorylation. The role of DBN1 and its phosphorylation will be also studied in diabetic mice with DKD using transgenic approach. These studies will help us to reveal new insights in the podocyte biology and the pathogenesis of DKD and identify potential new therapy for DKD.
题目:PP2A在足细胞生物学和糖尿病肾病中的作用

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A central role for mesangial cells in the initiation of diabetic nephropathy.
系膜细胞在糖尿病肾病的发生中起核心作用。
  • DOI:
    10.1016/j.kint.2023.03.033
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    19.6
  • 作者:
    Fang,Zhengying;Lee,Kyung;He,JohnCijiang
  • 通讯作者:
    He,JohnCijiang
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    $ 58.95万
  • 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:
    $ 58.95万
  • 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:
    $ 58.95万
  • 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:
    $ 58.95万
  • 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:
    10662465
  • 财政年份:
    2021
  • 资助金额:
    $ 58.95万
  • 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:
    $ 58.95万
  • 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:
    $ 58.95万
  • 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:
    $ 58.95万
  • 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
  • 资助金额:
    $ 58.95万
  • 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:
    10119964
  • 财政年份:
    2020
  • 资助金额:
    $ 58.95万
  • 项目类别:

相似海外基金

How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
  • 批准号:
    BB/Y004841/1
  • 财政年份:
    2024
  • 资助金额:
    $ 58.95万
  • 项目类别:
    Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
  • 批准号:
    BB/Y001427/1
  • 财政年份:
    2024
  • 资助金额:
    $ 58.95万
  • 项目类别:
    Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
  • 批准号:
    BB/Y005414/1
  • 财政年份:
    2024
  • 资助金额:
    $ 58.95万
  • 项目类别:
    Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
  • 批准号:
    10669829
  • 财政年份:
    2023
  • 资助金额:
    $ 58.95万
  • 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
  • 批准号:
    10587090
  • 财政年份:
    2023
  • 资助金额:
    $ 58.95万
  • 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
  • 批准号:
    10821599
  • 财政年份:
    2023
  • 资助金额:
    $ 58.95万
  • 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
  • 批准号:
    10841832
  • 财政年份:
    2023
  • 资助金额:
    $ 58.95万
  • 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
  • 批准号:
    10532480
  • 财政年份:
    2022
  • 资助金额:
    $ 58.95万
  • 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
  • 批准号:
    10741261
  • 财政年份:
    2022
  • 资助金额:
    $ 58.95万
  • 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
  • 批准号:
    10674894
  • 财政年份:
    2022
  • 资助金额:
    $ 58.95万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了