Pathophysiologic and specific Therapeutic Approaches of the Phospholipase A2 Receptor-mediated Membranous Nephropathy

• Applicant: Privatdozent Dr. Gunther Zahner
• Subject Area: Nephrology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451019656

Membranous nephropathy (MN) is one of the most common causes of glomerulonephritis in adults. Immune complexes appear to play a critical pathogenic role early in MN, associated with podocyte foot process effacement. Within one year of diagnosis, about one third of those with the disease remit spontaneously, while another third develop renal failure within ten years. In 2009, Larry Beck Jr. and David Salant achieved a milestone in MN research with the discovery of the first human autoantigen, phospholipase A2 receptor 1 (PLA2R1). PLA2R1 is responsible for about 75% of primary MN in adults. Diagnostic determination of anti-PLA2R1 autoantibodies has been established for identification and follow-up of PLA2R1-mediated MN quite fast. However, the pathogenic proof of anti-PLA2R1 antibodies was not achieved until 2019. The ectodomain of the 180-kD PLA2R1 consists of a cysteine-rich domain (CysR), a fibronectin type II domain (FnII), and eight so-called C-type lectin-like domains (CTLD). The immune dominant regions of the protein are mostly located within the first three N-terminal domains CysR, FnII and CTLD1. Additional binding sites of human autoantibodies have also been localized within the CTLD7 & 8 domains, which may be significant for disease severity. Since PLA2R1 is not expressed in either mouse or rat podocytes, we now established several PLA2R1-specific mouse models with different features. This project builds on the current funding phase. The following was elaborated: Work package 1: - Publication of the spontaneous PLA2R1-mediated MN model. - Publication of the PLA2R1-mediated, chPLA2R1-EAMN model. - Identification of two key time points (5 and 9 weeks after initial immunization, respectively) in the course of chPLA2R1-EAMN suitable for transcriptome and proteome studies. Work package 2: - Involvement of the complement system in chPLA2R1-EAMN. - Transcriptome and proteome proof of concept analyses. Work package 3: - In vitro characterization of PLA2R1-specific therapeutic antibodies. Therefore, the objective of the follow-up proposal is to get more insight in PLA2R1-dependent pathology and to develop specific therapies for PLA2R1-mediated membranous nephropathy. To perform this, we exclusively get access to our PLA2R1-specific models. During this project, we hope to improve the pathophysiological understanding of MN, as well as to successfully finish In vivo testing of our specific therapeutic antibodies.

• DFG Programme: Research Grants