Epigenetic Suppression of RASAL1 by HDAC3 and Cofactor YY1 Promotes Fibroblast–Myofibroblast Transition and Renal Fibrosis

TL;DR

This study shows that HDAC3 and YY1 suppress RASAL1, promoting kidney fibrosis, and suggests that targeting HDAC3 could help treat chronic kidney disease.

Contribution

The study identifies HDAC3 and YY1 as key regulators of RASAL1 suppression in fibroblast–myofibroblast transition and renal fibrosis.

Findings

HDAC3 suppresses RASAL1 expression during renal fibrosis in mouse models.

Pharmacological inhibition of HDAC3 reduces fibroblast transition and fibrosis.

YY1 co-regulates HDAC3's effect on RASAL1, highlighting a functional axis in fibrogenesis.

Abstract

Fibroblast–myofibroblast transition (FMT) and the resultant renal fibrosis are central pathological features of chronic kidney disease (CKD). Epigenetic suppression of RASAL1 (Ras protein activator like 1), an antifibrotic regulator in fibroblasts, is a key driver of this process. However, the underlying mechanisms are only partially understood. Here, we identify histone deacetylase 3 (HDAC3) as a critical epigenetic suppressor of RASAL1 expression in FMT of renal fibrosis. In mouse models of renal fibrosis induced by unilateral ureteral obstruction and aristolochic acid I, RASAL1 suppression coincided with a preferential increase in HDAC3. Fibroblast-specific Hdac3 knockout mice exhibited preserved RASAL1 expression, attenuated FMT, and reduced renal fibrosis compared to wild-type controls. Consistently, pharmacological inhibition of HDAC3 with RGFP966 similarly restored RASAL1 expression, inhibited FMT, and alleviated renal fibrotic pathology. In cultured renal fibroblasts, HDAC3 overexpression or inhibition by RGFP966 inversely affected RASAL1 abundance and major FMT parameters, which was coregulated by the repressive transcriptional factor YY1 (Yin Yang 1). Notably, targeted silencing of RASAL1 abrogated the antifibrotic effects of HDAC3 inhibition both in vitro and in vivo, underscoring the functional significance of the HDAC3–YY1–RASAL1 axis in FMT and fibrogenesis. Given that FMT is a conserved feature of fibrotic diseases across multiple organs, restoring RASAL1 expression via HDAC3 and YY1 modulation offers promising therapeutic strategies for CKD and potentially broader fibrotic disorders.

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