Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy
Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy
复制标题
补体 C3a 和 C3a 受体激活介导原发性膜性肾病机制中的足细胞损伤
DOI：
10.1681/asn.2021101384
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发表时间：
2022-07-01
影响因子：
13.6
通讯作者：
Zhao, Ming-hui
中科院分区：
文献类型：
--
作者：
Gao, Shuang;Cui, Zhao;Zhao, Ming-hui
背景 原发性膜性肾病 (MN) 中补体系统高度激活。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。方法检测MN患者肾脏C3aR表达及循环C3a水平。在暴露于 MN 血浆1/2C3aR 阻断剂（SB290157、JR14a）后评估人足细胞损伤。在第 0 天或蛋白尿后对患有海曼肾炎的大鼠施用 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。结果 在肾小球中，C3aR 染色与 podocin 融合良好。 C3aR 的过度表达与蛋白尿、血清肌酐和治疗无反应呈正相关。暴露于 MN 血浆的人足细胞显示 PLA2R、C3aR 和 Wnt3/b-catenin 表达增加，突触蛋白表达和迁移功能降低，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 阻断可减轻蛋白尿、电子致密沉积、足突宽度和肾小球基底膜增厚。血浆 C3a 水平升高和 C3aR 过度表达也得到缓解。特异性（而非总体）IgG 水平下降，肾小球中大鼠 IgG 沉积减少，随后 C1q、因子 B 和 C5b-9 减少。结论C3a过敏毒素是补体介导的MN足细胞损伤的重要效应物。 C3aR 拮抗剂可能是治疗这种疾病的潜在可行方法。
Background The complement system is highly activated in primary membranous nephropathy (MN). Iden-tifying 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. MethodsC3aR expression in kidneys and circulating levels of C3a of MN patients were examined. Human podocyte damage was assessed after exposure to MN plasma1/2C3aR 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. Results 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/b-catenin, reduced expression of synaptopodin and migration function, downregulated Bcl-2, and decreased cell viability. C3aR antagonistscould block these effects. In Heymann nephritis rats, C3aR blockade attenuated proteinuria, electron-dense deposition, foot process width, and glomerular basement membrane thickening in glomeruli. Thein creased 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. ConclusionC3a anaphylatoxin is a crucial effector of complement-mediated podocyte damage in MN. The C3aR antagonist may be a potentially viable treatment for this disease.