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WWP2 Exacerbates Podocyte Injury in Lupus Nephritis through Monoubiquitylating H2A at K119

ABSTRACT: Lupus nephritis (LN) is featured with podocyte injury and proteinuria. We previously demonstrated that WWP2, an E3 ubiquitin ligase, differentially regulated tubular injury and tubulointerstitial fibrosis. The present study aims to investigate WWP2’s implication in proteinuria and podocyte injury in LN. WWP2 increased in the glomerulus of LN kidneys, significantly correlating with proteinuria in LN. Intra-renal WWP2 knockdown alleviated proteinuria and podocyte injury in MRL/lpr mice. WWP2 overexpression significantly aggravated proteinuria in MRL/lpr mice. WWP2 deficiency in podocytes decreased proteinuria in nephrotoxic serum (NTS) mice model and alleviated podocyte injury induced by cytokines in vitro. Mechanistically, WWP2 potentially regulated systemic lupus erythematosus pathways attributing to its novel catalytic product, i.e., mono-ubiquitylated H2A K119 (ub-H2A). The pathological role of Ub-H2A remains largely unclear. Ub-H2A colocalized with WWP2 in the glomerulus and correlated with proteinuria. Decreasing ub-H2A effectively protected against podocyte injury and counteracted the aggravating effect of WWP2 on podocyte damage possibly through regulating actin dynamics. A novel WWP2 inhibitor prevented proteinuria in NTS model. Our data demonstrated that WWP2/ub-H2A exacerbated podocyte injury in LN by enhancing the actin dynamics disturbance. Antagonizing WWP2/ub-H2A signaling may be a novel therapeutic approach against LN.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308439 | GEO | 2026/09/09

REPOSITORIES: GEO

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