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). http://www.fasebj.org

Intravenous antagomiR‐494 lessens brain‐infiltrating neutrophils by increasing HDAC2‐mediated repression of multiple MMPs in experimental stroke

“…Noticeably, HDAC2 could bind to different loci on chromosome 11 and can modulate MMP27 bidirectionally. Previous studies suggested that the HDAC family could regulate multiple MMPs, including MMP1, MMP2, MMP3, MMP7, MMP9, MMP10, MMP13, MMP14, and MMP28, 23‐28 and that MMP10 could be regulated by HDAC3 and HDAC7 28,29 . For the first time, we found that HDAC2 could potentially modulate the MMP10, MMP16, MMP21, MMP25‐AS1, MMP27, and CD16 genes in neutrophils of AIS patients.…”

Intravenous antagomiR-494 lessens brain-infiltrating neutrophils by increasing HDAC2-mediated repression of multiple MMPs in experimental stroke

“…Noticeably, HDAC2 could bind to different loci on chromosome 11 and can modulate MMP27 bidirectionally. Previous studies suggested that the HDAC family could regulate multiple MMPs, including MMP1, MMP2, MMP3, MMP7, MMP9, MMP10, MMP13, MMP14, and MMP28 [20][21][22][23][24][25], and that MMP10 could be regulated by HDAC3 and HDAC7 [25,26]. For the first time, we found that HDAC2 could potentially modulate the MMP10, MMP16, MMP21, MMP25-AS1, and MMP27 genes in neutrophils of AIS patients.…”

Extracellular vesicles produced by bone marrow mesenchymal stem cells attenuate renal fibrosis, in part by inhibiting the RhoA/ROCK pathway, in a UUO rat model

“…Renal fibrosis develops in response to a host of insults such as growth factors and stress molecules, and the development goes through several important phases, including activation of renal interstitial fibroblasts, excessive and progressive accumulation of extracellular matrix (ECM) [22], EMT [23], inflammatory cell infiltration and tubular cell apoptosis [24]. During the chronic injury that occurs in CKD, continuous fibrotic matrix deposition will disrupt organ structure, suppress blood supply, affect organ function, and ultimately cause kidney failure [25,26].…”