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Targeting C3a/C5a Receptors Inhibits Human Mesangial Cell Proliferation and Alleviates IgA Nephropathy in Mice

Research output: Contribution to journalArticlepeer-review

Ying Zhang, Xianli Yan, Ting Zhao, Qihe Xu, Qi Peng, Ruimin Hu, Songxia Quan, Yali Zhou, Guolan Xing

Original languageEnglish
JournalClinical and Experimental Immunology
Early online date10 Apr 2017
DOIs
Accepted/In press28 Feb 2017
E-pub ahead of print10 Apr 2017

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Abstract

Complement activation has a deep pathogenic influence in IgA nephropathy (IgAN). C3a and C5a, small cleavage fragments generated by complement activation, are key mediators of inflammation. The fragments exert broad pro-inflammatory effects by binding to specific receptors (C3aR and C5aR, respectively). However, no studies thus far have investigated the effects of C3a, C5a and their receptors on IgAN. We observed that C3aR and C5aR antagonists repressed IgA-induced cell proliferation and IL-6 and MCP-1 production in cultured human mesangial cells (HMCs). Furthermore, an IgAN mouse model induced by Sendai virus infection was employed to investigate the effects of C3aR and C5aR on IgAN in vivo for the first time. Wild-type (WT) and several knockout mouse strains (C3aR(-/-) or C5aR(-/-) ) were immunised intranasally with increasing doses of inactivated virus for 14 weeks and were subjected to two intravenous viral challenges during the indicated time period. In the Sendai virus-induced IgAN model, C3aR/C5aR-deficient mice had significantly reduced proteinuria, lower renal IgA and C3 deposition, less histologic damage and reduced mesangial proliferation compared with WT mice. Both C3aR deficiency and C5aR deficiency, especially C3aR deficiency, significantly inhibited renal TNF-α, TGF-β, IL-1β, IL-6 and MCP-1 expression. However, C3aR/C5aR-deficient and WT mice with IgAN did not differ with respect to their BUN and SCr levels. Our findings provide further support for the idea that C3aR and C5aR are crucially important in IgAN and suggest that pharmaceutically targeting C3aR/C5aR may hold promise for the treatment of IgAN. This article is protected by copyright. All rights reserved.

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