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

基本信息

批准号：
10618308
负责人：
Stefano Da Sacco
金额：
$ 37.24万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618308
关键词：
Address Adult Albumins Animals Antibodies Antigens Autoantibodies Basement membrane Cell Communication Cells Characteristics Clinical Complement 3a Complement 3d Complement Activation Complement Inactivators Complement Membrane Attack Complex Cytoskeleton Data Deposition Development Disease Disease remission Endothelial Cells Endothelium Exposure to Extravasation Filtration Functional disorder Future Glomerulonephritis Human Immune Immunoglobulin G Impairment In Vitro Injury Intervention Trial Inulin Kidney Kidney Diseases Kidney Failure Knockout Mice MAP Kinase Gene MMP9 gene Mediating Membrane Membranous Glomerulonephritis Modeling Modification Molecular Multiple Trauma Mus NF-kappa B Nephrotic Syndrome Pathogenesis Pathway interactions Patients Permeability Pharmacologic Substance Phenotype Phospholipase A2 Placebos Play Production Proteins Proteinuria Randomized, Controlled Trials Rattus Receptor Signaling Role Serum Signal Transduction Snails System Testing Thrombospondins Work antagonist cell injury complement C3 precursor experimental study glomerular basement membrane glomerular endothelium glomerular filtration glomerulosclerosis human disease in vivo novel overexpression pharmacologic podocyte pre-clinical prevent receptor renal damage slit diaphragm therapeutic target tool translational study urinary

项目摘要

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.

原发性膜性肾病肾小球损伤的新机制原发性膜性肾病（MN）是成人肾病综合征的最常见原因。伤害是由针对足细胞抗原的循环自身抗体在足细胞上皮下空间的沉积引起基底膜，导致补体激活并形成 C5b-9 膜攻击复杂（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，一项随机对照试验表明抗 C5 抗体对患者疾病缓解没有益处与 MN，表明其他独立于 MAC 的机制也适用。 MN病理生理学研究由于缺乏可靠的体外系统而受到限制。我们生成了一个新的肾小球芯片平台将用作评估 MN 损伤替代机制的工具。初步数据表明，补充激活导致足细胞中的 C3a/C3aR 信号传导，从而导致肾小球通透选择性丧失 SNAIL 介导的信号传导。此外，挑战当前 MN 的假设，我们发现 MN 血清也在肾小球内皮细胞中导致 C3a/C3aR 信号转导，并诱导 MMP9，因此表明该信号传导在调节肾小球基底膜-细胞相互作用中的作用。这些作用可被 C3aR 拮抗剂阻止，表明 C3a 直接参与足细胞和 GEC 损伤和肾小球基底膜 (GBM) 降解。因此，根据我们的根据初步数据，我们假设 C3a/C3aR 信号传导不仅在足细胞损伤中发挥关键作用但也会对 GEC 产生影响，导致肾小球滤过屏障破坏和肾小球滤过屏障丧失渗透选择性。为了检验我们的假设，我们将研究 C3a 信号传导的影响及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，我们的发现不仅将提供新证据表明多种损伤机制在 PMN 中发挥作用，但也将告诉我们潜在的可能性可能被证明对开发 MN 和其他疾病新疗法有用的治疗靶点蛋白尿疾病。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The 2019 and 2021 International Workshops on Alport Syndrome.

DOI：
10.1038/s41431-022-01075-0
发表时间：
2022-05
期刊：
European journal of human genetics : EJHG
影响因子：
0
作者：
Daga S;Ding J;Deltas C;Savige J;Lipska-Ziętkiewicz BS;Hoefele J;Flinter F;Gale DP;Aksenova M;Kai H;Perin L;Barua M;Torra R;Miner JH;Massella L;Ljubanović DG;Lennon R;Weinstock AB;Knebelmann B;Cerkauskaite A;Gear S;Gross O;Turner AN;Baldassarri M;Pinto AM;Renieri A
通讯作者：
Renieri A

Decay-Accelerating Factor Restrains Complement Activation and Delays Progression of Murine cBSA-Induced Membranous Nephropathy.

DOI：
10.34067/kid.0000000000000122
发表时间：
2023-06-01
期刊：
Kidney360
影响因子：
0
作者：
Budge KL;Verlato A;Bin S;Salem FE;Perin L;La Manna G;Zaza G;Fiaccadori E;Cantarelli C;Cravedi P
通讯作者：
Cravedi P

Generation of a Glomerular Filtration Barrier on a Glomerulus-on-a-Chip Platform.

DOI：
10.1007/978-1-0716-1693-2_8
发表时间：
2021-09
期刊：
Methods in molecular biology
影响因子：
0
作者：
L. Perin;Stefano Da Sacco
通讯作者：
L. Perin;Stefano Da Sacco

C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy.

C3aR 启动的信号传导是膜性肾病足细胞损伤的关键机制。

DOI：
10.1172/jci.insight.172976
发表时间：
2024
期刊：
JCI insight
影响因子：
8
作者：
Zhang,Qi;Bin,Sofia;Budge,Kelly;Petrosyan,Astgik;Villani,Valentina;Aguiari,Paola;Vink,Coralien;Wetzels,Jack;Soloyan,Hasmik;LaManna,Gaetano;Podestà,ManuelAlfredo;Molinari,Paolo;Sedrakyan,Sargis;Lemley,KevinV;DeFilippo,Roger
通讯作者：
DeFilippo,Roger

Emerging Technologies to Study the Glomerular Filtration Barrier.