Anp32e mediates histone variant H2A.Z-regulated TGF-β1 involvement in renal interstitial fibrosis.

Renal interstitial fibrosis (RIF), a key pathological feature of chronic kidney disease, often leads to end-stage renal failure. However, the mechanisms underlying RIF remain unclear, and effective targeted therapies are still lacking. Our prior research identified that acidic nuclear phosphorylated protein 32 E (Anp32e) aggravates RIF, though the mechanism was not fully clarified. Anp32e is known as a histone chaperone regulating the histone variant H2A.Z, yet the role of H2A.Z in RIF and its connection to Anp32e remain largely unexplored. In this study, we observed elevated nuclear Anp32e in renal tubular epithelial cells in an RIF model. We further confirmed that Anp32e forms a protein complex with H2A.Z and showed that Anp32e may facilitates H2A.Z degradation via the proteasome pathway. Mechanistically, this degradation may reduce H2A.Z occupancy at the TGF-β1 promoter, leading to increased TGF-β1 expression and subsequent upregulation of fibrosis markers FN and Col-I. Collectively, our findings suggest that Anp32e may induces the degradation of H2A.Z via the ubiquitin-proteasome pathway, which contribute to increased transcriptional activity of TGF-β1 and subsequent promotion of RIF.