Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

Abstract

Renal fibrosis represents a key pathophysiological process in patients with chronic kidney diseases (CKD) and is typically associated with a poor prognosis. Renal tubular epithelial cells (RTECs), in response to a host of pro-fibrogenic stimuli, can trans-differentiate into myofibroblast-like cells and produce extracellular matrix proteins to promote renal fibrosis. In the present study we investigated the role of histone deacetylase 11 (HDAC11) in this process and the underlying mechanism. We report that expression levels of HDAC11 were up-regulated in the kidneys in several different animal models of renal fibrosis. HDAC11 was also up-regulated by treatment of Angiotensin II (Ang II) in cultured RTECs. Consistently, pharmaceutical inhibition with a smallmolecule inhibitor of HDAC11 (quisinostat) attenuated unilateral ureteral obstruction (UUO) induced renal fibrosis in mice. Similarly, HDAC11 inhibition by quisinostat or HDAC11 depletion by siRNA blocked Ang II induced pro-fibrogenic response in cultured RTECs. Mechanistically, HDAC11 interacted with activator protein 2 (AP-2α) to repress the transcription of Kruppel-like factor 15 (KLF15). In accordance, KLF15 knockdown antagonized the effect of HDAC11 inhibition or depletion and enabled Ang II to promote fibrogenesis in RTECs. Therefore, we data unveil a novel AP-2α-HDAC11-KLF15 axis that contributes to renal fibrosis.

Epigenetic Regulation of a Disintegrin and Metalloproteinase (ADAM) Transcription in Colorectal Cancer Cells: Involvement of β-Catenin, BRG1, and KDM4

“…BRG1 expression constructs ( Li et al, 2020a , b ), FLAG-tagged ADAM10 expression construct ( Parkin and Harris, 2009 ), ADAM17 expression construct ( Granato et al, 2018 ), and ADAM19 expression construct ( Chesneau et al, 2003 ) have been previously described. Transient transfections were performed with Lipofectamine 2000 (Invitrogen) as previously described ( Mao et al, 2020 ; Yang et al, 2020 ).…”

Epigenetic activation of the small GTPase TCL contributes to colorectal cancer cell migration and invasion

“…Whole-cell lysates were obtained by re-suspending cell pellets in RIPA buffer (50 mM Tris pH7.4, 150 mM NaCl, 1% Triton X-100) with freshly added protease inhibitor (Roche) as previously described [55][56][57][58][59] . Specific antibodies or pre-immune IgGs (P.I.I.)…”

BRG1 Activates PR65A Transcription to Regulate NO Bioavailability in Vascular Endothelial Cells

“…Of intrigue, ETS1 and BRG1 share a strikingly large number of target genes including MCP1, adhesion molecules, CTGF, and p21. Whereas ChIP-seq analysis has been performed for ETS1 in endothelial cells ( Mao et al, 2020 ), no such dataset is yet available for BRG1. BRG1 ChIP-seq experiments performed in several other cell types such as melanoma cells ( Lv et al, 2020 ) and epithelial cells ( Haesen et al, 2016 ) indeed reveal a preferential enrichment of ETS1 motifs in the BRG1 peaks.…”

“…Transient transfections were performed with Lipofectamine 2000 (Invitrogen). Luciferase activities were assayed 24–48 h after transfection using a luciferase reporter assay system (Promega) as previously described ( Li et al, 2019c ; Liu et al, 2019 ; Mao et al, 2020 ). Experiments were routinely performed in triplicate wells and repeated at least three times.…”