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 (DNMT)1-mediated maintenance of DNA methylation, the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in renal fibrosis remains unknown. In the present study, we observed the upregulation of UHRF1 in activated renal fibroblasts. Fibroblasts-specific depletion of UHRF1 reduced fibrotic lesions in both unilateral ureter obstruction- and unilateral renal ischemia-reperfusion injury-induced murine models of kidney fibrosis. Through Reduced Representation Bisulfite Sequencing, KLF15 was screened and further verified as the target methylated gene of UHRF1 and responsible for fibroblasts activation. Moreover, UHRF1 induced KLF15 methylation through interacting with DNMT1. Genetic depletion of UHRF1 or pharmacological inhibition the interaction decreased KLF15 methylation levels and restored its expression, resulting in reduced renal fibroblasts activation and kidney fibrosis. Collectively, our study suggests that UHRF1 might be a promising target for mitigating renal fibrosis. Overall design: RRBS-seq profiling of renal fibroblasts from wildtype mice. Fibroblasts were sorted from Sham group and UUO group at 7 days after operation.