Outer membrane vesicles derived from gut microbiota mediate tubulointerstitial inflammation: a potential new mechanism for diabetic kidney disease

被引：25

作者：

Chen, Pei Pei ^{[1
]}

Zhang, Jia Xiu ^{[1
]}

Li, Xue Qi ^{[1
]}

Li, Liang ^{[1
,2
]}

Wu, Qin Yi ^{[1
]}

Liu, Liang

Wang, Gui Hua ^{[1
]}

Ruan, Xiong Zhong ^{[3
]}

Ma, Kun Ling ^{[1
,4
]}

机构：

[1] Southeast Univ, Inst Nephrol, Sch Med, Zhongda Hosp, Nanjing 210009, Peoples R China

[2] Shandong First Med Univ, Peoples Hosp, Jinan 271100, Shandong, Peoples R China

[3] UCL, Sch Med, Dept Renal Med, John Moorhead Res Lab, Royal Free Campus, London NW3 2PF, England

[4] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Nephrol, Hangzhou 310003, Peoples R China

来源：

THERANOSTICS | 2023年 / 13卷 / 12期

基金：

中国国家自然科学基金;

关键词：

diabetic kidney disease; renal tubulointerstitial inflammation; gut microbiota; outer membrane vesicles; caspase-11; pathway; LPS; NEPHROPATHY; PROGRESSION; SULFATE;

D O I：

10.7150/thno.84650

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Rationale: Chronic tubulointerstitial inflammation is a common pathological process in diabetic kidney disease (DKD). However, its underlying mechanism is largely unknown. This study aims at investigating the role of gut microbiota-derived outer membrane vesicles (OMVs) in tubulointerstitial inflammation in DKD.Methods: Gut microbiota in diabetes mellitus rats was manipulated by microbiota depletion and fecal microbiota transplantation to explore its role in tubulointerstitial inflammation. To check the direct effects of OMVs, fecal bacterial extracellular vesicles (fBEVs) were administrated to mice orally and HK-2 cells in vitro. For mechanistic investigations, HK-2 cells were treated with small interfering RNA against caspase-4 and fBEVs pre-neutralized by polymyxin B.Results: By performing gut microbiota manipulation, it was confirmed that gut microbiota mediated tubulointerstitial inflammation in DKD. In diabetic rats, gut microbiota-derived OMVs were increased and were clearly detected in distant renal tubulointerstitium. Diabetic fBEVs directly administered by gavage translocated into tubular epithelial cells and induced tubulointerstitial inflammation and kidney injury. In vitro, OMVs were internalized through various endocytic pathways and triggered cellular inflammatory response. Mechanistically, it was revealed that OMVs-derived lipopolysaccharide induced tubular inflammation, which was mediated by the activation of the caspase-11 pathway.Conclusions: Increased OMVs due to dysbiosis translocated through leaky gut barrier into distant tubulointerstitium and induced cellular inflammation and renal tubulointerstitial injury in DKD. These findings enrich the mechanism understanding of how gut microbiota and its releasing OMVs influence the development and progression of kidney disease.

引用

页码：3988 / 4003

页数：16