C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy.
C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy.
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C3aR 启动的信号传导是膜性肾病足细胞损伤的关键机制。
DOI：
10.1172/jci.insight.172976
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发表时间：
2024
期刊：
影响因子：
8
通讯作者：
DeFilippo,Roger
中科院分区：
文献类型：
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作者：
Zhang,Qi;Bin,Sofia;Budge,Kelly;Petrosyan,Astgik;Villani,Valentina;Aguiari,Paola;Vink,Coralien;Wetzels,Jack;Soloyan,Hasmik;LaManna,Gaetano;Podestà,ManuelAlfredo;Molinari,Paolo;Sedrakyan,Sargis;Lemley,KevinV;DeFilippo,Roger
抗足细胞自身抗体在肾小球上皮下空间的沉积诱导原发性膜性肾病（MN），其是全球肾病综合征的主要原因。利用肾小球芯片系统，我们模拟了抗PLA 2 R抗体诱导的人原发性MN。在这里，我们表明，暴露的原代人足细胞表达PLA 2 R MN血清的结果在IgG沉积和补体激活其表面上，导致损失的芯片渗透选择性白蛋白。C3 a受体（C3 aR）拮抗剂以及C3 AR基因沉默足细胞减少MN血清诱导的氧化应激，并防止白蛋白泄漏。相反，抑制膜攻击复合物（MAC）的形成，以前认为在MN发病机制中发挥了重要作用，并没有影响白蛋白的渗透选择性。此外，用C3 aR拮抗剂治疗有效地防止了MN小鼠模型中的蛋白尿，证实了芯片的发现。总之，使用病理生理学相关的体外和体内模型的组合，我们建立了C3 a/C3 aR信号转导在补体介导的MN发病机制中起着关键作用，表明MN的替代治疗靶点。
The deposition of antipodocyte autoantibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN.