Mechanisms of complement-mediated podocyte injury in FSGS

总结 焦 失败 最近 的 显著 假设驱动 节段性肾小球硬化症（FSGS）是蛋白尿和肾功能衰竭的主要原因。 在超过50%的病例中导致终末期肾病（ESRD）。尽管 在理解FSGS的发病机制、机制方面的重要进展 疾病的发生和发展在很大程度上仍然是未知的。有限的功效和 与现有疗法相关的毒性迫切需要鉴定新的， 接近。 我们报道了新的发现，在阿霉素和CD 2AP-/-小鼠FSGS模型中， 补体调节因子衰变加速因子（decay accelerating factor，decay accelerating factor，decay accelerating factor）在足细胞上下调 膜，释放补体激活的限制，并导致 形成C3 a。足细胞上的C3 a/C3 aR信号传导导致细胞骨架 重排额外的初步数据表明，在患有FSGS的人类中， C3 a的下调和尿水平与蛋白尿和C3 d沉积相关， 肾小球这支持了这样的假设，即在鼠和人FSGS中， 和/或肾产生的补体成分通过 由β-淀粉样蛋白下调启动的替代途径并促进足细胞损伤， 肾小球硬化通过C3 a/C3 aR激活。我们将通过以下方式检验这一假设： 确定尿补体的来源（全身与肾脏）， 补体激活（替代，经典，或MBL），和体内效应 足细胞上的C3 a/C3 aR（目的1）。我们还将破译 机制（目标2）。 该研究项目的结果将为补体在 FSGS发病机制与结果无关。这些数据有可能解释 先前发表的观察结果表明， 有肾脏结局的FSGS患者。最后，结果可能会发生显着变化 临床实践，通过提供使用补体或 用于预防或延缓FSGS和其他疾病进展的补体受体抑制剂 蛋白尿性肾小球疾病。

Summary Focal failure recent of significant hypothesis-driven segmental glomerulosclerosis (FSGS) is a major cause of proteinuria and renal that leads to end stage renal disease (ESRD) in over 50% of the cases. Despite important advances in the understanding of FSGS etiopathogenesis, mechanisms disease initiation and progression are still largely unknown. Limited efficacy and toxicities associated with existing therapies urge for the identification of new, approaches. We reported the novel finding that, in Adriamycin and CD2AP-/- murine models of FSGS, complement regulator decay accelerating factor (DAF) is downregulated on podocyte membranes, which unleashes restraints to complement activation and leads to the formation of C3a. Signaling of C3a/C3aR on podocytes results into cytoskeleton rearrangement. Additional preliminary data indicate that, in humans with FSGS, DAF is downregulated and urinary levels of C3a correlate with proteinuria and C3d deposition in the glomeruli. This supports the hypothesis that, in murine and human FSGS, filtered and/or kidney-produced complement components undergo activation through the alternative pathway initiated by DAF downregulation and promote podocyte injury and glomerulosclerosis through C3a/C3aR activation. We will test this hypothesis by determining the source of urinary complement (systemic versus renal), the pathway of complement activation (alternative, classical, or MBL), and the in vivo effect of C3a/C3aR on podocytes (aim 1). We will also decipher the implicated molecular mechanisms (aim 2). The results of the research project will provide new insight on the role of complement in FSGS pathogenesis regardless of outcome. The data have the potential to explain previously published observations associating complement deposition in the glomeruli of patients with FSGS with renal outcomes. Finally, the results could significantly change clinical practice through providing supporting evidence for the use of complement or complement receptor inhibitors to prevent or retard progression of FSGS and other proteinuric glomerular diseases.