Renal Division, Peking University First Hospital, Beijing, China.
Institute of Nephrology, Peking University, Beijing, China.
J Am Soc Nephrol. 2022 Sep;33(9):1742-1756. doi: 10.1681/ASN.2021101384. Epub 2022 Jul 1.
The complement system is highly activated in primary membranous nephropathy (MN). Identifying the complement components that damage podocytes has important therapeutic implications. This study investigated the role of C3a and the C3a receptor (C3aR) in the pathogenesis of MN.
C3aR expression in kidneys and circulating levels of C3a of MN patients were examined. Human podocyte damage was assessed after exposure to MN plasma +/- C3aR blockade (SB290157, JR14a). C3aR antagonists were administered to rats with Heymann nephritis on day 0 or after proteinuria. Clinical and pathologic parameters, specific IgG and complement activation, and podocyte injuries were then assessed.
In the glomeruli, C3aR staining merged well with podocin. Overexpression of C3aR correlated positively with proteinuria, serum creatinine, and no response to treatments. Human podocytes exposed to MN plasma showed increased expression of PLA2R, C3aR, and Wnt3/-catenin, reduced expression of synaptopodin and migration function, downregulated Bcl-2, and decreased cell viability. C3aR antagonists could block these effects. In Heymann nephritis rats, C3aR blockade attenuated proteinuria, electron-dense deposition, foot process width, and glomerular basement membrane thickening in glomeruli. The increased plasma C3a levels and overexpression of C3aR were also alleviated. Specific, but not total, IgG levels decreased, with less deposition of rat IgG in glomeruli and subsequent reduction of C1q, factor B, and C5b-9.
C3a anaphylatoxin is a crucial effector of complement-mediated podocyte damage in MN. The C3aR antagonist may be a potentially viable treatment for this disease.
补体系统在原发性膜性肾病（MN）中高度激活。鉴定损伤足细胞的补体成分具有重要的治疗意义。本研究探讨了 C3a 和 C3a 受体（C3aR）在 MN 发病机制中的作用。
检测 MN 患者肾脏中 C3aR 的表达和循环 C3a 水平。在 MN 血浆存在或不存在 C3aR 阻断剂（SB290157、JR14a）的情况下，评估人足细胞损伤。在 Heymann 肾炎大鼠中，在第 0 天或蛋白尿后给予 C3aR 拮抗剂。然后评估临床和病理参数、特异性 IgG 和补体激活以及足细胞损伤。
在肾小球中，C3aR 染色与足突蛋白吻合良好。C3aR 的过表达与蛋白尿、血清肌酐和无反应治疗呈正相关。暴露于 MN 血浆的人足细胞表现出 PLA2R、C3aR 和 Wnt3/-catenin 的表达增加，突触蛋白和迁移功能降低，Bcl-2 下调，细胞活力降低。C3aR 拮抗剂可以阻断这些作用。在 Heymann 肾炎大鼠中，C3aR 阻断减轻蛋白尿、电子致密物沉积、足突宽度和肾小球基底膜增厚。血浆 C3a 水平升高和 C3aR 过表达也得到缓解。特异性但非总 IgG 水平降低，肾小球中大鼠 IgG 沉积减少，随后 C1q、因子 B 和 C5b-9 减少。
C3a 过敏毒素是 MN 中补体介导的足细胞损伤的关键效应因子。C3aR 拮抗剂可能是治疗这种疾病的潜在有效方法。
