The roles of phospholipase A2 receptor 1 and thrombospondin type-1 domain-containing 7A in Membranous Nephropathy

The discoveries of the phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) as endogenous antigens in about 80% of patients with membranous nephropathy (MN) allow to study the pathogenic mechanisms leading to the development of this disease. In this project, we intend to establish rodent models of MN involving PLA2R1 and THSD7A. Due to the lack of expression of PLA2R1 on rodent podocytes, we generated a transgenic mouse line that expresses the extracellular part of the human PLA2R1 on podocytes. Our preliminary studies demonstrate that upon exposure to PLA2R1 antibodies these mice develop glomerular lesions very similar to the ones in human MN. On the other hand, THSD7A is endogenously expressed on mouse and rat podocytes, facilitating its investigation as an antigen in MN. We were recently able to show that human THSD7A antibodies induce MN-like morphology and proteinuria in mice. Using these mouse models of MN, we plan to further investigate the functions of PLA2R1 and THSD7A in the pathophysiology of glomerular injury in MN. We intend to define the roles of antibody subclasses, activation of complement, murine genetic background, and potential influence on intracellular signaling pathways in PLA2R1- and THSD7A-mediated podocyte injury and MN development. With these approaches we aim to better understand the cellular and molecular mechanisms how these two endogenous antigens lead to the onset and progression of MN.

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