Inhibition of epigenetic regulator UHRF1 attenuates renal fibrosis and retains transcription factor Krüppel-like factor 15 expression

Aberrant DNA methylation modification is well-known to be involved in renal fibrogenesis. As a critical cooperator in DNA methyltransferase 1 (DNMT1)-mediated maintenance of DNA methylation, the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in renal fibrosis remains unknown. Here, upregulation of UHRF1 is observed in activated renal fibroblasts. Fibroblasts-specific depletion of UHRF1 reduces fibrotic lesions in both unilateral ureter obstruction- and unilateral renal ischemia-reperfusion injury-induced murine models of kidney fibrosis. Through Reduced Representation Bisulfite Sequencing, Krüppel-like factor 15 (KLF15) is screened and further verified as the target methylated gene of UHRF1 and responsible for fibroblasts activation. Moreover, UHRF1 induces KLF15 methylation through interacting with DNMT1. Genetic depletion of UHRF1 or pharmacological inhibition of such interaction decreases KLF15 methylation levels and restores its expression, resulting in reduced renal fibroblasts activation and kidney fibrosis. Collectively, these results suggest that UHRF1 may be a promising target for mitigating renal fibrosis.