Zhang Y, Yan X, Zhao T, Xu Q, Peng Q, Hu R, Quan S, Zhou Y, Xing G
Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Medical Research Council Centre for Transplantation, King's College London, London, UK.
Clin Exp Immunol. 2017 Jul;189(1):60-70. doi: 10.1111/cei.12961. Epub 2017 Apr 10.
Complement activation has a deep pathogenic influence in immunoglobulin (Ig)A nephropathy (IgAN). C3a and C5a, small cleavage fragments generated by complement activation, are key mediators of inflammation. The fragments exert broad proinflammatory 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 interleukin (IL)-6 and monocyte chemotactic protein 1 (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 knock-out mouse strains (C3aR or C5aR ) were immunized intranasally with increasing doses of inactivated virus for 14 weeks and were subjected to two intravenous viral challenges during the time-period indicated. In the Sendai virus-induced IgAN model, C3aR/C5aR-deficient mice had significantly reduced proteinuria, lower renal IgA and C3 deposition, less histological damage and reduced mesangial proliferation compared with WT mice. Both C3aR deficiency and C5aR deficiency, especially C3aR deficiency, inhibited renal tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-β, IL-1β, IL-6 and MCP-1 expression significantly. However, C3aR/C5aR-deficient and WT mice with IgAN did not differ with respect to their blood urea nitrogen (BUN) and serum creatinine 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.
补体激活在免疫球蛋白A（IgA）肾病（IgAN）中具有深远的致病影响。C3a和C5a是补体激活产生的小裂解片段，是炎症的关键介质。这些片段分别通过与特定受体（C3aR和C5aR）结合发挥广泛的促炎作用。然而，迄今为止尚无研究调查C3a、C5a及其受体对IgAN的影响。我们观察到，C3aR和C5aR拮抗剂可抑制培养的人系膜细胞（HMCs）中IgA诱导的细胞增殖以及白细胞介素（IL）-6和单核细胞趋化蛋白1（MCP-1）的产生。此外，首次采用仙台病毒感染诱导的IgAN小鼠模型在体内研究C3aR和C5aR对IgAN的影响。野生型（WT）小鼠和几种基因敲除小鼠品系（C3aR或C5aR基因敲除）经鼻内接种递增剂量的灭活病毒，持续14周，并在所示时间段内接受两次静脉内病毒攻击。在仙台病毒诱导的IgAN模型中，与WT小鼠相比，C3aR/C5aR基因缺陷小鼠的蛋白尿显著减少，肾脏IgA和C3沉积降低，组织学损伤减轻，系膜增殖减少。C3aR缺陷和C5aR缺陷，尤其是C3aR缺陷，均显著抑制肾脏肿瘤坏死因子（TNF）-α、转化生长因子（TGF）-β、IL-1β、IL-6和MCP-1的表达。然而，C3aR/C5aR基因缺陷的IgAN小鼠和WT IgAN小鼠在血尿素氮（BUN）和血清肌酐水平方面并无差异。我们的研究结果进一步支持了C3aR和C5aR在IgAN中至关重要的观点，并表明以C3aR/C5aR为药物靶点可能为IgAN的治疗带来希望。
