Genetic and pharmaceutical targeting of Suv39h1 ameliorates renal fibrosis by unlocking CXCL10 transcription [I]

Renal fibrosis is present in all forms of chronic kidney disease (CKD) and when dysregulated contributes to renal failure. Renal fibroblast is the major precursor to myofibroblast, the effector cell type of renal fibrosis. In the present study we investigated the role of Suv39h1, a lysine methyltransferase, in fibroblast-myofibroblast transition (FMyT) and renal fibrosis. We report that Su39h1 is up-regulated during FMyT both in vitro and in vivo. Suv39h1 deletion in fibroblasts partially blocked FMyT in vitro and attenuated renal fibrosis in three different animal models. Additionally, conditional Suv39h1 knockout in Postn+ mature myofibroblasts mitigated renal fibrosis in mice. Importantly, Suv39h1 inhibition with a small-molecule compound chaetocin suppressed FMyT in cell culture and ameliorated renal fibrosis in mice. Transcriptomic analysis uncovered CXCL10 as a downstream target for Suv39h1. CXCL10 knockdown nullified the protective effect of Suv39h1 insufficiency on renal fibrosis. Mechanistically, CXCL10 regulated FMyT by suppressing the Hippo/YAP pathway. In conclusion, our data illustrate a previously unrecognized role for Suv39h1 in regulating renal fibrosis.