Abstract: SA-PO0729
WWP2 Exacerbates Podocyte Injury in Lupus Nephritis Through Monoubiquitylating H2A at K119
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- You, Ran, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiang, Yuteng, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jia, Zhanjun, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Zhang, Aihua, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Group or Team Name
- Aihua Zhang's Group.
Background
Lupus nephritis (LN), characterized by podocyte injury and proteinuria, is a severe complication of systemic lupus erythematosus (SLE). We previously demonstrated that WWP2, an E3 ubiquitin ligase, differentially regulated tubular injury and tubulointerstitial fibrosis. Here, we elucidated the role and underlying mechanisms of WWP2 in proteinuria in LN.
Methods
We analyzed renal biopsies from LN patients and employed podocyte-specific Wwp2 knockout (cKO) mice, two nephritis mouse models (nephrotoxic serum (NTS)-induced and MRL/lpr spontaneous autoimmune strain), and human podocyte culture to elucidate the implication of WWP2 in LN. Multi-omics approaches (ubiquitylation omics, proteomics, CUT&Tag sequencing) were used to investigate the mechanism.
Results
WWP2 was upregulated in LN glomeruli and significantly correlated with proteinuria in patients with LN. Silencing WWP2 markedly alleviated LN, as evidenced by WWP2 cKO in podocytes decreasing proteinuria by 32.5% in the NTS model and intrarenal WWP2 knockdown reducing proteinuria by 55.6% in MRL/lpr mice. Parallel to proteinuria, WWP2 deletion significantly attenuated glomerular sclerosis and podocyte injury in mice models. WWP2 overexpression worsened the disease. Consistently, WWP2 knockout directly protected against podocyte injury induced by cytokines in cell culture while WWP2 overexpression exacerbated it. Ubiquitylation omics and experimental validation by co-immunoprecipitation, in vivo and in vitro ubiquitylation assays showed that WWP2 may mediate LN via mono-ubiquitylation of H2A K119 (ub-H2A). Glomerular Ub-H2A correlated with proteinuria in LN patients. Reducing ub-H2A blocked WWP2’s detrimental effect on podocyte injury. Mechanistically, actin dynamics disturbance may mediate the effect of WWP2/Ub-H2A in podocyte injury. We also developed a novel WWP2 inhibitor that protected against nephrotoxic nephritis in mice.
Conclusion
Our data demonstrated that WWP2 exacerbated podocyte injury in LN by promoting ub-H2A-dependent actin dysregulation. Antagonizing WWP2/Ub-H2A signaling may be a promising therapeutic strategy for LN.