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

补体旁路途径的不受控制的激活是多发性骨髓瘤发病机制的核心。 肾脏疾病因子H是旁路途径的主要循环调节剂。它包含两个约束力 区域，以及这些区域之一中的突变（称为短共有重复序列19 - 20，或SCR 19 - 20）。 20)与非典型溶血性尿毒症综合征有关。因此，SCR 19 - 20被认为是介导 因子H与内皮细胞的结合。因子H缺陷也与其他肾脏疾病有关， 包括C3肾小球病、IgA肾病和狼疮性肾炎。此外，一组蛋白质， 拮抗因子H，称为因子H相关蛋白（FHRs），与肾脏疾病有关。 然而，我们还没有一个统一的理解，为什么不同的遗传变异的H因子或 FHR引起肾小球损伤的不同超微结构模式。也不知道为什么肾脏如此 在具有系统性因子H突变的患者中特别容易受到损伤。因此，更大的理解是 需要了解这些蛋白质如何相互作用以及与肾脏的相互作用。在上一个供资期间， 在这项研究中，我们发现肾脏内产生的一种蛋白质，膜联蛋白A2， 因子H区域，SCR 6 - 8。膜联蛋白A2的过表达引起补体激活， 肾脏，证明SCR 6 - 8对于控制肾脏表面上的补体活化是关键的。 有趣的是，许多与疾病相关的FHR变异体都含有该结合区域的重复。 基于这些发现，该资助的中心假设是SCR 6 - 8对于控制 肾小球基底（GBM）上的旁路途径激活，SCR 19 - 20对于控制肾小球基底（GBM）的炎症至关重要。 激活内皮细胞。干扰这些结合区域的突变或蛋白质使 C3G和aHUS患者。为了检验这一假设，将追求以下具体目标。 目的1）鉴定控制肾表面补体活化的分子因子。我们将在 我们将直接测试SCR 6 - 8是否介导因子H与GBM的结合，并鉴定 结合配体。目的2）测试FHR和膜联蛋白A2是否引起补体失调。 肾我们将使用动物模型来检验FHR和膜联蛋白A2引起补体激活的假设。 在肾脏内的特定表面上活化。目的3）开发新的补体阻断疗法 激活肾脏。在这个目标中，我们将测试新的治疗策略是否可以特异性地抑制 在肾脏中的补体激活，同时保持其他激活机制完整。这个项目是 创新，因为它提供了一个合理的系统，了解如何在众多报告的缺陷， 因子H有助于多种不同的肾脏疾病，它提供了一个解释，为什么肾脏 所以特别容易受到替代途径介导的损伤。这项资助的研究意义重大 因为他们测试了专门在肾脏内阻断补体激活的新治疗策略。

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.