A Novel Insight into the Role of PLA2R and THSD7A in Membranous Nephropathy

Figure 2

The hypothetical pathogenesis model of the relationship between the tumor and thrombospondin domain-containing 7A- (THSD7A-) associated membranous nephropathy (MN). (a) In theory, THSD7A acts as a potential tumor-associated antigen that is overexpressed by cancerous tissue allowing regional exposure of pathogenic epitopes of the autoantigen, which contributes to the production of anti-THSD7A antibodies. The extrarenal anti-THSD7A antibodies circulate into the glomerular capillaries and bind to THSD7A antigens located on podocytes. Besides, the tumor may alter the renal microenvironment that induces antigen conformational changes that allow binding of anti-THSD7A antibodies. (b) Pathogenicity of anti-THSD7A antibodies causing podocyte injury and proteinuria. The binding of anti-THSD7A antibodies to THSD7A on podocytes disrupts the slit diaphragm that allows albumin excretion into the urine, collapse of the actin cytoskeleton, and reduction of detachment from GBM. (c) The normal structure of podocyte foot processes. THSD7A that is present in foot processes closest to the slit diaphragm is involved in the stabilization of the slit diaphragm of mature podocytes, which forms the final barrier to albumin permeation. Abbreviations: APC: antigen-presenting cell; TCR: T cell receptor; MHC: major histocompatibility complex; GBM: glomerular basement membrane.