Microtubule associated protein 4 phosphorylation-induced epithelial-to-mesenchymal transition of podocyte leads to proteinuria in diabetic nephropathy

作者全名："Li, Lingfei; Feng, Yanhai; Zhang, Junhui; Zhang, Qiong; Ren, Jun; Sun, Cheng; Li, Shujing; Lei, Xia; Luo, Gaoxing; Hu, Jiongyu; Huang, Yuesheng"

作者地址："[Li, Lingfei; Lei, Xia] Third Mil Med Univ, Army Med Univ, Daqing Hosp, Dept Dermatol, Chongqing, Peoples R China; [Li, Lingfei; Feng, Yanhai; Zhang, Qiong; Luo, Gaoxing; Hu, Jiongyu; Huang, Yuesheng] Third Mil Med Univ, Inst Burn Res, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China; [Li, Lingfei; Feng, Yanhai; Zhang, Qiong; Luo, Gaoxing; Huang, Yuesheng] Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China; [Ren, Jun] Fudan Univ, Dept Cardiol, Shanghai Inst Cardiovasc Dis, Zhongshan Hosp, Shanghai 200032, Peoples R China; [Ren, Jun] Univ Washington, Dept Lab Med & Pathol, Seattle, WA 98195 USA; [Sun, Cheng] Third Mil Med Univ, Dept Ophthalmol, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China; [Li, Shujing] Chongqing Med Univ, Affiliated Hosp 2, Chongqing, Peoples R China; [Zhang, Junhui; Hu, Jiongyu] Third Mil Med Univ, Endocrinol Dept, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China; [Huang, Yuesheng] Southern Univ Sci & Technol, Dept Wound Repair, Southern Univ Sci & Technol Hosp, Inst Wound Repair & Regenerat Med,Sch Med, Shenzhen, Peoples R China"

通信作者："Luo, GX; Hu, JY; Huang, YS (通讯作者)，Third Mil Med Univ, Inst Burn Res, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China.; Luo, GX; Huang, YS (通讯作者)，Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China.; Hu, JY (通讯作者)，Third Mil Med Univ, Endocrinol Dept, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China.; Huang, YS (通讯作者)，Southern Univ Sci & Technol, Dept Wound Repair, Southern Univ Sci & Technol Hosp, Inst Wound Repair & Regenerat Med,Sch Med, Shenzhen, Peoples R China."

来源：CELL COMMUNICATION AND SIGNALING

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000832707700001

JCR分区：Q1

影响因子：8.4

年份：2022

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：MAP4; Diabetic nephropathy; Proteinuria; Epithelial-to-mesenchymal transition; Apoptosis

摘要："Background: Diabetic nephropathy (DN) involves various structural and functional changes because of chronic glycemic assault and kidney failure. Proteinuria is an early clinical manifestation of DN, but the associated pathogenesis remains elusive. This study aimed to investigate the role of microtubule associated protein 4 (MAP4) phosphorylation (p-MAP4) in proteinuria in DN and its possible mechanisms. Methods: In this study, the urine samples of diabetic patients and kidney tissues of streptozotocin (STZ)-induced diabetic mice were obtained to detect changes of p-MAP4. A murine model of hyperphosphorylated MAP4 was established to examine the effect of MAP4 phosphorylation in DN. Podocyte was applied to explore changes of kidney phenotypes and potential mechanisms with multiple methods. Results: Our results demonstrated elevated content of p-MAP4 in diabetic patients' urine samples, and increased kidney p-MAP4 in streptozocin (STZ)-induced diabetic mice. Moreover, p-MAP4 triggered proteinuria with aging in mice, and induced epithelial-to-mesenchymal transition (EMT) and apoptosis in podocytes. Additionally, p-MAP4 mice were much more susceptible to STZ treatment and showed robust DN pathology as compared to wild-type mice. In vitro study revealed high glucose (HG) triggered elevation of p-MAP4, rearrangement of microtubules and F-actin filaments with enhanced cell permeability, accompanied with dedifferentiation and apoptosis of podocytes. These effects were significantly reinforced by MAP4 hyperphosphorylation, and were rectified by MAP4 dephosphorylation. Notably, pretreatment of p38/MAPK inhibitor SB203580 reinstated all HG-induced pathological alterations. Conclusions: The findings indicated a novel role for p-MAP4 in causing proteinuria in DN. Our results indicated the therapeutic potential of MAP4 in protecting against proteinuria and related diseases."

基金机构："State Key Laboratory of Trauma, Burns and Combined Injury Research Foundation [SKLYQ201802]; Young Scientists Fund of the National Natural Science Foundation of China [82003323]; Military Medical Innovation Program in Daping Hospital [2019CXJSC014]"

基金资助正文："This study was supported by the State Key Laboratory of Trauma, Burns and Combined Injury Research Foundation (No. SKLYQ201802), and the project supported by the Young Scientists Fund of the National Natural Science Foundation of China (No. 82003323), and the Military Medical Innovation Program in Daping Hospital (2019CXJSC014)."