Exacerbation of renal interstitial fibrosis by the UHRF1/G9a axis through epigenetic silencing of KLF15

Renal fibrosis represents a central pathological driver of chronic kidney disease (CKD), yet the epigenetic mechanisms remain incompletely understood. This study identifies a critical role for the Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1)/G9a axis in this process. We demonstrated that both UHRF1 and the histone methyltransferase G9a are significantly upregulated in fibrotic kidneys from CKD patients and relevant murine models by means of multiple experimental approaches, as well as in activated renal fibroblasts. Fibroblast-specific knockout of UHRF1 markedly attenuated renal fibrosis and concurrently suppressed the expression and enzymatic activity of G9a. Mechanistically, we revealed the pathological mechanism that the UHRF1/G9a axis is associated with the deposition of repressive histone H3 lysine 9 mono-/di-methylation (H3K9me1/me2) marks at the promoter of the anti-fibrotic gene Krüppel-like factor 15 (KLF15), as supported by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) and cleavage under targets and tagmentation (CUT&Tag) assays, leading to KLF15 transcriptional silencing. Restoration of KLF15 protein expression upon inhibition of this axis contributed to the amelioration of fibrosis. Collectively, our findings indicate the UHRF1/G9a epigenetic complex as a key regulator of renal fibrosis and highlight its potential as a novel target for alleviating renal fibrosis.