2. Academic Validation
  3. Macrophages promote heat stress nephropathy in mice via the C3a-C3aR-TNF pathway

Macrophages promote heat stress nephropathy in mice via the C3a-C3aR-TNF pathway

  • Immunobiology. 2023 Jan 18;228(2):152337. doi: 10.1016/j.imbio.2023.152337.
Yang Yang 1,  Dongjuan Zhang 2,  Minghui Song 3,  Chao Wang 4,  Jiayi Lv 5,  Jie Zhou 6,  Meihan Chen 7,  Lu Ma 4,  Changlin Mei 8
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Nephrology, The 981(th) Hospital of Joint Logistic Support Force, Chengde, China.
  • 3 Clinical Laboratory, Hainan Hospital of General Hospital of Chinese People's Liberation Army, Sanya, China.
  • 4 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.
  • 5 Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China.
  • 6 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.
  • 7 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.
  • 8 Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, The Navy Military Medical University, Shanghai, China. Electronic address: chlmei1954@126.com.
PMID: 36689826 DOI: 10.1016/j.imbio.2023.152337
Abstract

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-α, which induced renal tubular epithelial cell (RTEC) Apoptosis in vivo and in vitro. Interestingly, C3a treatment failed to directly induce TNF-α production and Apoptosis in RTECs. However, TNF-α 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-α 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.

Keywords

Apoptosis; Complement; Heat stress nephropathy; Macrophage; Tumor necrosis factor.

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