Complement-mediated injury of the kidney: New mechanisms and novel therapies

补体替代途径的失控激活是多发性硬化症发病机制的核心 肾脏疾病。因子H是另一种途径的主要循环调节因子。它包含两个绑定 区域和其中一个区域的突变(称为短共识重复19-20，或SCR 19- 20)与非典型溶血性尿毒症综合征有关。因此，SCR 19-20被认为是调解 H因子与内皮细胞的结合。H因子缺陷也与其他肾脏疾病有关， 包括C3肾小球病变、IgA肾病、狼疮性肾炎。此外，一组蛋白质可以 拮抗H因子，称为H因子相关蛋白(FHR)，与肾脏疾病有关。 然而，我们还没有一个统一的认识，为什么不同的遗传变异的因子H或 FHR导致肾小球损伤的不同超微结构模式。也不知道为什么肾脏会这样 在系统性因子H突变的患者中，唯一容易受到伤害的。因此，更多的理解是 需要了解这些蛋白质如何相互作用以及如何与肾脏相互作用。在上一个资助期内 在这笔赠款中，我们发现肾脏内产生的一种蛋白质--膜联蛋白A2--阻止了另一种结合 因子H的区域，Scr 6-8。膜联蛋白A2的过度表达导致补体在整个 这表明ScR 6-8对于控制肾脏表面的补体激活至关重要。 有趣的是，许多与疾病相关的FHR变体都包含这个结合区的重复。 基于这些发现，这项研究的中心假设是SCR6-8对于控制 肾小球基底膜(GBM)和ScR 19-20的替代途径激活对控制至关重要 对内皮细胞的激活。干扰这些结合区的突变或蛋白质易于发生 患者分别为C3G和AHUS。为了验证这一假设，我们将追求以下具体目标。 目的1)确定控制肾表面补体活化的分子因素。我们将在 体外系统我们将直接测试ScR6-8是否介导因子H与GBM的结合并鉴定 结合的配体。目的2)检测FHR和Annexin A2是否导致补体失调 肾脏。我们将使用动物模型来检验FHR和Annexin A2导致补体的假设 肾脏内特定表面的激活。目的3)开发阻断补体的新疗法 肾脏的激活。在这个目标中，我们将测试新的治疗策略是否能够特异性地抑制 在保持其他激活机制不变的同时，肾脏中的补体被激活。这个项目是 创新，因为它提供了一个合理的系统，用于理解 因子H导致多种不同的肾脏疾病，它解释了为什么肾脏是 因此非常容易受到其他途径介导的损伤。这笔赠款中的研究具有重要意义 因为他们测试了阻止补体激活的新治疗策略，特别是在肾脏内。

Uncontrolled activation of the alternative pathway of complement is central to the pathogenesis of multiple kidney diseases. Factor H is the main circulating regulator of the alternative pathway. It contains two binding regions, and mutations in one of these regions (referred to as Short Consensus Repeat 19-20, or SCR 19- 20) are associated with atypical hemolytic uremic syndrome. Thus, SCR 19-20 is believed to mediate binding of factor H to endothelial cells. Factor H defects are also associated with other kidney diseases, including C3 glomerulopathy, IgA nephropathy, and lupus nephritis. Furthermore, a group of proteins that antagonize factor H, called the factor H related proteins (FHRs), are associated with kidney disease. However, we do not yet have a unified understanding of why the different genetic variants in factor H or the FHRs cause distinct ultrastructural patterns of glomerular injury. It is also not known why the kidney is so uniquely vulnerable to injury in patients with systemic factor H mutations. Thus, greater understanding is needed regarding how these proteins interact with each other and with the kidney. In the last funding period of this grant we discovered that a protein produced within the kidney, annexin A2, blocks the other binding region of factor H, SCR 6-8. Overexpression of annexin A2 causes complement activation throughout the kidney, demonstrating that SCR 6-8 is critical for controlling complement activation on kidney surfaces. Interestingly, many disease-associated variants of the FHRs contain reduplications of this binding region. Based on these findings, the central hypothesis of this grant is that SCR 6-8 is critical for controlling alternative pathway activation on the glomerular basement (GBM), and SCR 19-20 is critical for controlling activation on endothelial cells. Mutations or proteins that interfere with these binding regions predispose patients to C3G and aHUS, respectively. To test this hypothesis, the following specific aims will be pursued. Aim 1) Identify the molecular factors that control complement activation on renal surfaces. We will use in vitro systems to we will directly test whether SCR 6-8 mediates binding of factor H to the GBM and identify the binding ligands. Aim 2) Test whether the FHRs and annexin A2 cause complement dysregulation in the kidney. We will use animal models to test the hypothesis that the FHRs and annexin A2 cause complement activation on specific surfaces within the kidney. Aim 3) Develop novel therapies for blocking complement activation in the kidney. In this aim we will test whether new therapeutic strategies can specifically inhibit complement activation in the kidney while leaving other mechanisms of activation intact. This project is innovative because it provides a rational system for understanding how the numerous reported defects in factor H contribute to multiple different kidney diseases, and it provides an explanation for why the kidney is so uniquely susceptible to alternative pathway-mediated injury. The studies in this grant are significant because they test new treatment strategies for blocking complement activation specifically within the kidney.