Novel mechanisms of glomerular injury in primary membranous nephropathy

原发性膜性肾病肾小球损伤的新机制 原发性膜性肾病(MN)是成人肾病综合征最常见的原因。伤病是 由足细胞抗原的循环自身抗体在足细胞上皮下间隙沉积而起 基底膜，导致补体活化，形成C5b-9膜攻击 复杂(MAC)。Mac介导的亚溶解损伤被认为会导致足细胞损伤和肾小球破裂。 然而，一项随机对照试验显示，抗C5抗体对患者的疾病缓解没有好处。 对于MN，建议适用于其他MAC独立机制。MN的病理生理学研究有 由于缺乏可靠的体外系统而受到限制。我们创造了一个新的芯片上的肾小球平台，我们 将被用作评估MN损伤的替代机制的工具。初步数据显示，补体 激活导致足细胞中的C3a/C3aR信号转导，从而导致肾小球膜选择性的丧失 到蜗牛介导的信号传递。此外，挑战MN目前的假设，我们发现 锰血清也可诱导肾小球内皮细胞C3a/C3aR信号转导，并诱导肾小球内皮细胞过度表达 MMP9，提示该信号在调节肾小球基底膜-细胞间的相互作用中起作用。 这些效应可被C3aR拮抗剂阻止，提示C3a直接参与足细胞和 GEC损伤和肾小球基底膜(GBM)降解。因此，基于我们的 初步数据我们假设C3a/C3aR信号不仅在足细胞损伤中起关键作用 但也对GEC发挥作用，导致肾小球滤过屏障的破坏和肾小球滤过率的丧失。 渗透性选择性。为了验证我们的假设，我们将研究C3a信号的作用，其机制(S) 在体内和体外对GBM降解的作用和作用。如果得到证实，我们的发现不仅将提供 多种损伤机制在PMN中发挥作用的新证据，但也将告知我们潜在的 可证明对开发治疗MN和其他疾病的新疗法有用的治疗靶点 蛋白尿疾病。

Novel mechanisms of glomerular injury in primary membranous nephropathy Primary membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Injury is initiated by the deposition of circulating auto-antibodies against podocyte antigens in the subepithelial space of the basement membrane, leading to complement activation and formation of the C5b-9 membrane attack complex (MAC). MAC-mediated sublytic injury is thought to cause podocyte damage and glomerular disruption. However, a randomized controlled trial showed no benefit of anti-C5 antibody in disease remission in patients with MN, suggesting that other MAC-independent mechanisms apply. Studies on MN pathophysiology have been limited by the lack of reliable in vitro systems. We generated a new glomerulus-on-a-chip platform that we will use as a tool to assess alternative mechanisms of injury in MN. Preliminary data suggest that complement activation leads to C3a/C3aR signaling in podocytes, which induces loss of glomerular permselectivity due to SNAIL-mediated signaling. Moreover, challenging current assumption in MN, we have found that MN-serum leads to C3a/C3aR signaling also in glomerular endothelial cells and induces overexpression of MMP9, thus suggesting a role of this signaling in regulating glomerular basement membrane-cell interaction. These effects are prevented by a C3aR antagonist, suggesting the direct involvement of C3a in podocyte and GEC damage and in glomerular basement membrane (GBM) degradation. Therefore, based on our preliminary data we hypothesize that C3a/C3aR signaling not only plays a critical role in podocyte damage but exert its effects also on GEC, leading to disruption of glomerular filtration barrier and loss of permselectivity. To test our hypothesis, we will investigate the effects of C3a signaling, its mechanism(s) of action and its role in GBM degradation both in vitro and in vivo. If confirmed, our findings will not only provide novel evidence that multiple injury mechanisms are in play in PMN but will also inform us about potential therapeutic targets that could prove useful for the development of new treatments for MN and other proteinuric diseases.