Abstract
Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.
Highlights
Membranous nephropathy (MN) constitutes the main cause of nephrotic syndrome in nondiabetic white adults [1]
After identifying TNFRSF12a (Fn14) as one of the highest expressed TNF receptor superfamily (TNFRSF) in podocytes in vivo and as highly upregulated in glomeruli in human MN, we explored the impact of its ligand TWEAK on podocyte phospholipase A2 receptor (PLA2R) expression in cultured cells and in vivo and demonstrated that TWEAK-induced podocyte PLA2R upregulation is prevented by tacrolimus
Once TNFRSF12a/Fn14 was identified among the highest expressed TNFRSF genes in podocytes in vivo and the most upregulated in glomeruli in human MN, the impact of its ligand TWEAK on podocyte PLA2R expression was explored in mice and in cultured human podocytes and the impact of tacrolimus on TWEAK-induced PLA2R expression was explored in cultured human podocytes
Summary
Membranous nephropathy (MN) constitutes the main cause of nephrotic syndrome in nondiabetic white adults [1]. Most patients with primary MN have IgG4 circulating antibodies against the podocyte membrane M-type phospholipase A2 receptor (PLA2R), leading to subepithelial deposition of PLA2R-anti-PLA2R immune complexes [5,6]. A complex multi-hit process encompassing both genetic factors and environmental exposures has been proposed [10] In this setting, the immune system may have an important role by stimulating the production of antibodies, and by upregulating PLA2R expression [9]. Characterization of the factors regulating podocyte PLA2R expression could impact our understanding of disease pathogenesis and contribute to optimizing therapeutic strategies. In this regard, whether calcineurin inhibitors modulate podocyte PLA2R expression has not been explored so far
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