PMID- 36689826 OWN - NLM STAT- MEDLINE DCOM- 20230307 LR - 20230316 IS - 1878-3279 (Electronic) IS - 0171-2985 (Linking) VI - 228 IP - 2 DP - 2023 Mar TI - Macrophages promote heat stress nephropathy in mice via the C3a-C3aR-TNF pathway. PG - 152337 LID - S0171-2985(23)00005-0 [pii] LID - 10.1016/j.imbio.2023.152337 [doi] AB - Heat-stress nephropathy (HSN) is associated with recurrent dehydration. However, the mechanisms underlying HSN remain largely unknown. In this study, we evaluated the role of dehydration in HSN and kidney injury in mice. Firstly, we found that complement was strongly activated in the mice that were exposed to dehydration; and among complement components, the interaction between C3a and its receptor, C3aR, was more closely associated with kidney injury. Then two-month-old mice were intraperitoneally injected with 2% dimethyl sulfoxide (DMSO) or the C3aR inhibitor SB290157 during dehydration. DMSO-treated mice exhibited excessive macrophage infiltration, renal cell apoptosis, and kidney fibrosis. In contrast, SB290157-treated mice had no apparent kidney injury. By fluorescence-activated cell sorting (FACS), we found that SB290157 treatment in mice remarkably inhibited macrophage infiltration and suppressed CCR2 expression in macrophages. In addition, C3a binding to C3aR promoted macrophage polarization toward the M1 phenotype and increased the production of TNF-alpha, which induced renal tubular epithelial cell (RTEC) apoptosis in vivo and in vitro. Interestingly, C3a treatment failed to directly induce TNF-alpha production and apoptosis in RTECs. However, TNF-alpha production in response to C3a treatment was significantly elevated when RTECs were cocultured with macrophages, suggesting that macrophages rather than RTECs are the target of C3a-C3aR interaction. At last, we proved that infusion of macrophages which highly expressed TNF-alpha would significantly deteriorate HSN in TNF-KO mice when they were exposed to recurrent dehydration. This study uncovers a novel mechanism underlying the pathogenesis of HSN, and a potential pathway to prevent kidney injury during dehydration. CI - Copyright (c) 2023. Published by Elsevier GmbH. FAU - Yang, Yang AU - Yang Y AD - Department of Nephrology, The 981(th) Hospital of Joint Logistic Support Force, Chengde, China; Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China. Electronic address: yybjzy@163.com. FAU - Zhang, Dongjuan AU - Zhang D AD - Department of Nephrology, The 981(th) Hospital of Joint Logistic Support Force, Chengde, China. FAU - Song, Minghui AU - Song M AD - Clinical Laboratory, Hainan Hospital of General Hospital of Chinese People's Liberation Army, Sanya, China. FAU - Wang, Chao AU - Wang C AD - Kidney Diagnostic and Therapeutic Center of the Chinese People's Liberation Army, Beidaihe Rehabilitation and Recuperation Center of the Chinese People's Liberation Army, Qinhuangdao, China. FAU - Lv, Jiayi AU - Lv J AD - Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China. FAU - Zhou, Jie AU - Zhou J AD - Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China; Department of Nephrology, Affiliated ShuGuang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. FAU - Chen, Meihan AU - Chen M AD - Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China; Department of Nephrology, Shanghai Tenth People's Hospital, TongJi University, Shanghai, China. FAU - Ma, Lu AU - Ma L AD - Kidney Diagnostic and Therapeutic Center of the Chinese People's Liberation Army, Beidaihe Rehabilitation and Recuperation Center of the Chinese People's Liberation Army, Qinhuangdao, China. FAU - Mei, Changlin AU - Mei C AD - Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China. Electronic address: chlmei1954@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230118 PL - Netherlands TA - Immunobiology JT - Immunobiology JID - 8002742 RN - 0 (SB 290157) RN - 0 (Tumor Necrosis Factor-alpha) RN - YOW8V9698H (Dimethyl Sulfoxide) RN - 80295-42-7 (Complement C3a) RN - 0 (Receptors, Complement) SB - IM MH - Animals MH - Mice MH - *Tumor Necrosis Factor-alpha MH - Dehydration MH - Dimethyl Sulfoxide MH - Complement C3a/genetics/metabolism MH - *Kidney Diseases MH - Macrophages/metabolism MH - Receptors, Complement/genetics OTO - NOTNLM OT - Apoptosis OT - Complement OT - Heat stress nephropathy OT - Macrophage OT - Tumor necrosis factor COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/01/24 06:00 MHDA- 2023/03/08 06:00 CRDT- 2023/01/23 18:05 PHST- 2022/08/27 00:00 [received] PHST- 2022/12/14 00:00 [revised] PHST- 2023/01/16 00:00 [accepted] PHST- 2023/01/24 06:00 [pubmed] PHST- 2023/03/08 06:00 [medline] PHST- 2023/01/23 18:05 [entrez] AID - S0171-2985(23)00005-0 [pii] AID - 10.1016/j.imbio.2023.152337 [doi] PST - ppublish SO - Immunobiology. 2023 Mar;228(2):152337. doi: 10.1016/j.imbio.2023.152337. Epub 2023 Jan 18.