Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1

被引:7
作者
Zeng, Yan [1 ,2 ,3 ,4 ]
Guo, Man [2 ,3 ,4 ]
Wu, Qi [1 ,3 ,4 ,5 ]
Tan, Xiaozhen [2 ,3 ,4 ,6 ]
Jiang, Chunxia [1 ,2 ,3 ,4 ]
Teng, Fangyuan [2 ,3 ,4 ,6 ]
Chen, Jiao [2 ,3 ,4 ]
Zhang, Fanjie [7 ]
Ma, Xiumei
Li, Xinyue [8 ,9 ,10 ]
Gu, Junling [11 ]
Huang, Wei [2 ,3 ,4 ]
Zhang, Chunxiang [12 ]
Law, Betty Yuen-Kwan [1 ]
Long, Yang [2 ,3 ,4 ,6 ]
Xu, Yong [1 ,2 ,3 ,4 ]
机构
[1] Macau Univ Sci & Technol, Fac Chinese Med, Dr Nehers Biophys Lab Innovat Drug Discovery, State Key Lab Qual Res Chinese Med, Ave Wai Long, Taipa 999078, Macau, Peoples R China
[2] Southwest Med Univ, Affiliated Hosp, Dept Endocrinol & Metab, Luzhou 646000, Sichuan, Peoples R China
[3] Metab Vasc Dis Key Lab Sichuan Prov, Luzhou 646000, Sichuan, Peoples R China
[4] Sichuan Clin Res Ctr Nephropathy, Luzhou 646000, Sichuan, Peoples R China
[5] Southwest Med Univ, Dept Pathol, Affiliated Hosp, Luzhou 646000, Sichuan, Peoples R China
[6] Southwest Med Univ, Affiliated Hosp, Expt Med Ctr, Luzhou 646000, Sichuan, Peoples R China
[7] Southwest Med Univ, Affiliated Hosp, Dept Crit Care Med, Luzhou 646000, Sichuan, Peoples R China
[8] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu 610000, Sichuan, Peoples R China
[9] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Lab Med, Chengdu 610000, Sichuan, Peoples R China
[10] Chengdu Med Coll, Affiliated Hosp 2, China Natl Nucl Corp Hosp 416, Chengdu 610000, Sichuan, Peoples R China
[11] Sichuan Univ, West China Yibin Hosp, Yibin Peoples Hosp 2, Dept Endocrinol, Yibin 644000, Sichuan, Peoples R China
[12] Southwest Med Univ, Affiliated Hosp, Inst Cardiovasc Res, Basic Med Res Innovat Ctr Cardiometab Dis,Dept Car, Luzhou 646000, Sichuan, Peoples R China
关键词
Indole-3-propionic acid; SIRT1; Oxidative stress; Mitochondria; Diabetic kidney disease; Glomerular endothelial cells; OXIDATIVE STRESS; PGC-1-ALPHA; ACTIVATION; KINASE; DYSFUNCTION; RESOLUTION; PODOCYTES; COMPLEX;
D O I
10.1016/j.jare.2024.08.018
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Introduction: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. Objectives: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. Methods: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. Results: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT10s role in promoting PGC-1a deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. Conclusion: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
引用
收藏
页码:607 / 630
页数:24
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