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。损伤是 由针对足细胞抗原的循环自身抗体在上皮下间隙中的沉积引发， 基底膜，导致补体激活并形成C5b-9膜攻击 复合物（MAC）。MAC介导的亚溶解性损伤被认为会导致足细胞损伤和肾小球破坏。 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益处 与MN，这表明其他MAC独立的机制适用。关于MN病理生理学的研究已经 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肾小球芯片平台， 将用作评估MN损伤的替代机制的工具。初步数据显示， 激活导致足细胞中的C3a/C3aR信号传导，其诱导肾小球渗透选择性的丧失， SNAIL介导的信号传导。此外，挑战MN中当前的假设，我们发现， MN-血清也在肾小球内皮细胞中导致C3a/C3aR信号传导，并诱导C3a/C3aR的过度表达。 MMP9，从而表明该信号在调节肾小球基底膜-细胞相互作用中的作用。 这些作用被C3aR拮抗剂阻止，表明C3a直接参与足细胞， GEC损伤和肾小球基底膜（GBM）降解。因此，根据我们的 初步数据表明，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破坏和肾小球滤过功能丧失。 选择渗透性为了验证我们的假设，我们将研究C3a信号传导的作用，其机制， 作用及其在体外和体内GBM降解中的作用。如果得到证实，我们的发现不仅能提供 新的证据表明，多种损伤机制在PMN中起作用，但也将告知我们潜在的 治疗靶点，可以证明对MN和其他疾病的新治疗方法的开发有用。 蛋白尿性疾病

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.