Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role

Abstract

Membranous nephropathy (MN) is the major cause of nephrotic syndrome with special pathological features, caused by the formation of immune complexes in the space between podocytes and the glomerular basement membrane. In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A). Formation of antibodies against PLA2R1 is much more common, accounting for 70-80% of IMN. However, the mechanism of anti-podocyte antibody production in IMN is still unclear. In this review, we emphasize that the exposure of PLA2R1 is critical for triggering the pathogenesis of PLA2R1-associated MN, and propose the potential association between inflammation, pollution and PLA2R1. Our review aims to clarify the current research of these precipitating factors in a way that may suggest future directions for discovering the pathogenesis of MN, leading to additional therapeutic targets and strategies for the prevention and early treatment of MN.

Keywords: PLA2R1; PM2.5; immunological pathogenesis; kidney; lung; membranous nephropathy.

Figure 1

History of the study of membranous nephropathy. (A) Basic pathological features of MN. Illustration of the progression of glomerular lesions in MN (left) with four early studies describing its basic pathological features (right). (B) Studies of experimental MN and important results. Ten seminal studies of experimental MN (left) and the major discoveries relating to development of MN, including immune complex deposition and complement activation (right). (C) Recent advances in our understanding of MN. Three major podocyte antigens found in human MN (left), and other major work on MN since 2000 (right).

Figure 2

Hypothetical model for the effect of inflammation on PLA2R1. (A) Effect of redox conditions on PLA2R1. PLA2R1 without disulfide bond under reducing condition (Green) and with disulfide bond under non-reducing condition (Red). (B) The potential endocytic property of human PLA2R1. We hypothesize that the extracellular domain of PLA2R1 binds to phospholipase A2 and is transported into the cell by receptor-mediated endocytosis. This model has yet to be supported by any direct evidence. (C) Inflammation, PM2.5, and oxidative microenvironments. We hypothesize that inflammation, including that associated with PM2.5, alters the microenvironment of PLA2R1-expressing cells. PLA2R1 exposed to this oxidative microenvironment may form or retain disulfide bonds resulting the long-term expression of pathogenic epitopes.

Figure 3

Hypothetical model of the relationship between PM2.5 and membranous nephropathy. (A) Hypothesis of how PM2.5 induces anti-PLA2R1 antibody production. PM2.5 in the airways and alveoli causes an inflammatory response involving neutrophils, alveolar macrophages, and airway epithelial cells. We hypothesize that these cells may express PLA2R1, that due to oxidative stress associated with inflammation, may assume a conformation that includes pathogenic epitopes that contribute to the formation of autoantibodies. Alternatively, PLA2R1 may be released into the inflammatory space during the release of extracellular traps. PLA2R1 may then be bound by antigen presenting cells, triggering the humoral immune response, and producing anti-PLA2R1 antibodies. (B) The hypothetical process of subepithelial immune complex deposition caused by the anti-PLA2R1 antibody exogenous to glomeruli. Both PM2.5 and anti-PLA2R1 antibodies enter blood vessel and circulate into the glomerular capillaries. The anti-PLA2R1 antibodies penetrate the endothelial cells and glomerular basement membrane (GBM), recognize and bind to naturally-expressed PLA2R1 on podocytes to form the immune complex. These complexes then deposit into the space between podocytes and GBM.