The pathogenic role of succinate-SUCNR1: a critical function that induces renal fibrosis via M2 macrophage

作者全名："Pu, Min; Zhang, Jing; Hong, Fuyan; Wang, Yan; Zhang, Chengwei; Zeng, Yongcheng; Fang, Zhenzhen; Qi, Weiwei; Yang, Xia; Gao, Guoquan; Zhou, Ti"

作者地址："[Pu, Min; Zhang, Jing; Hong, Fuyan; Wang, Yan; Zhang, Chengwei; Zeng, Yongcheng; Fang, Zhenzhen; Qi, Weiwei; Yang, Xia; Gao, Guoquan; Zhou, Ti] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem & Mol Biol, Guangzhou, Peoples R China; [Gao, Guoquan] Sun Yat Sen Univ, Affiliated Guangzhou Women & Childrens Hosp, Zhongshan Sch Med, Program Mol Med, Guangzhou, Peoples R China; [Qi, Weiwei; Yang, Xia; Gao, Guoquan; Zhou, Ti] Sun Yat sen Univ, Guangdong Engn & Technol Res Ctr Gene Manipulat &, Guangzhou, Peoples R China; [Yang, Xia; Zhou, Ti] Sun Yat Sen Univ, China Key Lab Trop Dis Control, Minist Educ, Guangzhou, Peoples R China; [Gao, Guoquan] Sun Yat Sen Univ, Zhongshan Sch Med, Guangdong Prov Key Lab Brain Funct & Dis, Guangzhou, Peoples R China; [Gao, Guoquan] Guangdong Prov Key Lab Diabetol, Guangzhou, Guangdong, Peoples R China; [Pu, Min] Chongqing Med Univ, Affiliated Hosp 2, Chongqing Key Lab Ultrasound Mol Imaging, Dept Ultrasound, Chongqing 400010, Peoples R China"

通信作者："Gao, GQ; Zhou, T (通讯作者)，Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem & Mol Biol, Guangzhou, Peoples R China.; Gao, GQ (通讯作者)，Sun Yat Sen Univ, Affiliated Guangzhou Women & Childrens Hosp, Zhongshan Sch Med, Program Mol Med, Guangzhou, Peoples R China.; Gao, GQ; Zhou, T (通讯作者)，Sun Yat sen Univ, Guangdong Engn & Technol Res Ctr Gene Manipulat &, Guangzhou, Peoples R China.; Zhou, T (通讯作者)，Sun Yat Sen Univ, China Key Lab Trop Dis Control, Minist Educ, Guangzhou, Peoples R China.; Gao, GQ (通讯作者)，Sun Yat Sen Univ, Zhongshan Sch Med, Guangdong Prov Key Lab Brain Funct & Dis, Guangzhou, Peoples R China.; Gao, GQ (通讯作者)，Guangdong Prov Key Lab Diabetol, Guangzhou, Guangdong, Peoples R China."

来源：CELL COMMUNICATION AND SIGNALING

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001157492300001

JCR分区：Q2

影响因子：8.4

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："BackgroundRenal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis.MethodsMale C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms.ResultsSuccinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3 beta/beta-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells.ConclusionsThe causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3 beta/beta-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1."

基金机构：Sun-Yat Sen University

基金资助正文：The NRK-49F cell line was generously provided by Professor Jing Nie from Southern Medical University. Professor Jun Chen generously provided the BMDM cell from Sun-Yat Sen University. We express our gratitude for her enthusiastic assistance.