Dimethyl fumarate attenuates LPS induced septic acute kidney injury by suppression of NFκB p65 phosphorylation and macrophage activation

Yun Tang; Chan Wang; Shasha Chen; Li Li; Xiang Zhong; Jiong Zhang; Yunlin Feng; Lin Wang; Jie Chen; Meidie Yu; Fang Wang; Li Wang; Guisen Li; Yarong He; Yi Li

doi:10.1016/j.intimp.2021.108395

Dimethyl fumarate attenuates LPS induced septic acute kidney injury by suppression of NFκB p65 phosphorylation and macrophage activation

Int Immunopharmacol. 2022 Jan:102:108395. doi: 10.1016/j.intimp.2021.108395. Epub 2021 Dec 13.

Authors

Yun Tang¹, Chan Wang², Shasha Chen³, Li Li⁴, Xiang Zhong³, Jiong Zhang³, Yunlin Feng³, Lin Wang⁵, Jie Chen⁶, Meidie Yu¹, Fang Wang³, Li Wang³, Guisen Li⁷, Yarong He⁸, Yi Li⁹

Affiliations

¹ Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.
² Department of Nephrology, Nuclear Industry 416 Hospital, Chengdu, Sichuan 610041, China.
³ Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, Sichuan, China.
⁴ Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
⁵ Institute of Laboratory Animal Sciences, School of Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.
⁶ Central laboratory, School of Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.
⁷ Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, Sichuan, China. Electronic address: GuisenLi@med.uestc.edu.cn.
⁸ Emergency Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: heyarong@scu.edu.cn.
⁹ Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, Sichuan, China. Electronic address: liyisn@med.uestc.edu.cn.

PMID: 34915410
DOI: 10.1016/j.intimp.2021.108395

Abstract

Septic acute kidney injury (AKI) always accounts for high mortality of septic patients in ICU. Due to its not well understood mechanism for infection and immune-regulation in kidney dysfunction, there is a lack of effective therapy without side effects. Dimethyl fumarate (DMF) as an immunomodulatory molecule has been approved for treatment to multiple sclerosis. However, the therapeutic effect and immunomodulatory role underlying DMF action in septic AKI is unclear. This study aimed to elucidate the role of DMF in lipopolysaccharide (LPS)-induced septic AKI involving macrophage regulation. In current study, we administered DMF by oral gavage to mice with LPS-induced AKI, then harvested serum and kidney at three different time points. We further isolated Bone marrow-derived macrophages (BMDMs) from mice and stimulated them with LPS followed by DMF treatment. To explore immunomodulatory role of DMF in macrophages, we depleted macrophages in mice using liposomal clodronate after DMF treatment upon LPS-induced septic AKI. Then we observed that DMF attenuated renal dysfunction and murine pathological kidney injury after LPS injection. DMF could inhibit translocation of phosphorylated NF-κB p65 and suppress macrophage activation in LPS-induced AKI. DMF reduced the secretion of TNF-α and IL-6 whereas increased the secretion of IL-10 and Arg-1 in BMDMs after LPS stimulation. DMF also inhibited NF-κB p65 phosphorylation in BMDMs after LPS stimulation. Importantly, the effect of DMF against LPS-induced AKI, macrophage activation, and translocation of phosphorylated NF-κB p65 was impaired upon macrophage depletion. Thus, DMF could attenuate LPS-induced septic AKI by suppression of NF-κB p65 phosphorylation and macrophage activation. This work suggested the potential therapeutic role of DMF for patients in ICU threatened by septic AKI.

Keywords: DMF; Inflammation; Macrophage activation; NF-κB p65 phosphorylation; Septic AKI.

MeSH terms

Acute Kidney Injury / chemically induced
Acute Kidney Injury / drug therapy*
Acute Kidney Injury / immunology
Acute Kidney Injury / metabolism
Animals
Enzyme-Linked Immunosorbent Assay
Female
Glutamates / therapeutic use*
Lipopolysaccharides / pharmacology
Macrophage Activation / drug effects*
Mice
Mice, Inbred BALB C
Microscopy, Confocal
Phosphorylation
Transcription Factor RelA / metabolism*

Substances

Glutamates
Lipopolysaccharides
Transcription Factor RelA
glutamic acid dimethyl ester