C3a Mediates Epithelial-to-Mesenchymal Transition in Proteinuric Nephropathy
C3a Mediates Epithelial-to-Mesenchymal Transition in Proteinuric Nephropathy
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DOI：
10.1681/asn.2008040434
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发表时间：
2009-03-01
影响因子：
13.6
通讯作者：
Sheerin, Neil S.
中科院分区：
文献类型：
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作者：
Tang, Ziyong;Lu, Bao;Sheerin, Neil S.
小管间质炎症和进行性纤维化是导致蛋白尿肾病肾衰竭的常见途径。在临床和动物研究中，补体系统的激活与小管间质损伤的发生有关，但补体诱导肾损伤的机制尚不完全清楚。在这里，我们研究了补体对小管上皮细胞表型的影响。暴露于血清蛋白的小管上皮细胞具有间充质细胞的表型和功能特征。E-cadherin蛋白表达降低，或平滑肌肌动蛋白和I型胶原mRNA表达升高。将细胞暴露于补体过敏毒素C3a诱导了类似的特征。用C3a受体（C3aR）拮抗剂治疗可阻止C3a和血清诱导的上皮细胞向间质细胞转化。在阿霉素诱导的蛋白尿模型中，与野生型小鼠相比，c3ar缺陷小鼠表现出更小的损伤，保留了肾功能，并提高了存活率。此外，c3ar缺陷小鼠肾脏间质胶原I和cc-平滑肌肌动蛋白明显减少。综上所述，补体过敏毒素C3a是肾小球和小管间质损伤的重要介质，可诱导小管上皮细胞向间质细胞转变。
Tubulointerstitial inflammation and progressive fibrosis are common pathways that lead to kidney failure in proteinuric nephropathies. Activation of the complement system has been implicated in the development of tubulointerstitial injury in clinical and animal studies, but the mechanism by which complement induces kidney injury is not fully understood. Here, we studied the effect of complement on the phenotype of tubular epithelial cells. Tubular epithelial cells exposed to serum proteins adopted phenotypic and functional characteristics of mesenchymal cells. Expression of E-cadherin protein decreased and expression of both or-smooth muscle actin protein and collagen I mRNA increased. Exposure of the cells to the complement anaphylotoxin C3a induced similar features. Treating with a C3a receptor (C3aR) antagonist prevented both C3a- and serum-induced epithelial-to-mesenchymal transition. In the adriamycin-induced proteinuria model, C3aR-deficient mice demonstrated less injury, preserved renal function, and improved survival compared with wild-type mice. Furthermore, the kidneys of C3aR-deficient mice had significantly less interstitial collagen I and cc-smooth muscle actin. In summary, the complement anaphylotoxin C3a is an important mediator of glomerular and tubulointerstitial injury and can induce tubular epithelial-to-mesenchymal transition.