Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

ABSTRACT In this study, we examined the effect of MC1568, a selective class IIa histone deacetylase (HDAC) inhibitor, on the development and progression of renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO). All 4 class IIa HDAC isoforms, in particular HDAC4, were up‐regulated in renal epithelial cells of the injured kidney. Administration of MC1568 immediately after UUO injury reduced expression of α–smooth muscle actin (α‐SMA), fibronectin, and collagen 1. MC1568 treatment or small interfering RNA–mediated silencing of HDAC4 also suppressed expression of those proteins in cultured renal epithelial cells. Mechanistically, MC1568 abrogated UUO‐induced phosphorylation of Smad3, NF‐κB, and up‐regulation of integrin a Vβ6 in the kidney and inhibited TGF‐β1‐induced responses in cultured renal epithelial cells. MCI568 also increased renal expression of klotho, bone morphogenetic protein 7, and Smad7. Moreover, delayed administration of MC1568 at 3 d after ureteral obstruction reversed the expression of α‐SMA, fibronectin, and collagen 1 and increased expression of matrix metalloproteinase (MMP)‐2 and ‐9. Collectively, these results suggest that selectively targeting class IIa HD AC isoforms (in particular HDAC4) may inhibit development and progression of renal fibrosis by suppressing activation and expression of multiple prof ibrotic molecules and increasing expression of antif ibrotic proteins and MMPs.—Xiong, C., Guan, Y., Zhou, X., Liu, L., Zhuang, M. A., Zhang, W., Zhang, Y., Masucci, M. V., Bayliss, G., Zhao, T. C., Zhuang, S. Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis. FASEB J. 33,8249–8262 (2019). www.fasebj.org