Genetic and pharmaceutical targeting of Suv39h1 ameliorates renal fibrosis by unlocking CXCL10 transcription.

INTRODUCTION Identified as a pathological hallmark of all forms of chronic kidney disease (CKD), renal fibrosis contributes to renal failure when dysregulated. In this process, renal fibroblasts act as the primary source of myofibroblasts, which play a pivotal role as the central effector cells.

Objectives

This study identifies a critical role for the lysine methyltransferase Suv39h1 in regulating fibroblast-myofibroblast transition (FMyT) and renal fibrosis.

Methods

Fibroblast- and myofibroblast-specific gene knockout in mice was achieved using the Col1a2-CreERT2 and Postn-CreERT2 drivers. The model of renal fibrosis was established by unilateral ureteral obstruction (UUO) or streptozotocin-induced diabetic nephropathy (DN). Transcriptomic alterations were evaluated by RNA-seq.

Results

Our data indicate that the transcriptional upregulation of Su39h1 may be implicated in the process of FMyT, as evidenced by its consistent induction in both employed model systems. Suv39h1 deletion attenuated renal fibrosis in three animal models, consistent with its inhibition of FMyT in fibroblasts. Moreover, the conditional ablation of Suv39h1 within Postn-expressing mature myofibroblasts resulted in a significant abrogation of the pathological remodeling associated with renal fibrosis in mice. Notably, the targeted inhibition of the histone methyltransferase Suv39h1 by chaetocin effectively suppresses fibroblast activation in vitro and ameliorates the pathological progression of renal fibrosis in a murine model. Transcriptomic analysis revealed CXCL10 as a downstream target of Suv39h1. Furthermore, CXCL10 knockdown abolished the protective effect of Suv39h1 insufficiency on renal fibrosis. Mechanistically, CXCL10 regulated FMyT by suppressing the Hippo/YAP pathway.

Conclusion

We identify Suv39h1-mediated regulation as a previously unrecognized facet of renal fibrogenesis.