title: Class I histone deacetylase activity is required for proliferation of renal epithelial cells.
abstract: The process of renal regeneration after acute kidney injury is thought to recapitulate renal development, and proliferation of renal proximal tubular cells (RPTCs) is a critical step in the regenerative response. Recent studies indicate that class I histone deacetylases (HDACs) are required for embryonic kidney gene expression, growth, and differentiation. The role and underlying mechanisms of class I HDAC activation in RPTC proliferation, however, remain unclear. In this study, we used cultured RPTCs to examine this issue since four class I HDAC isoforms (1, 2, 3, and 8) are abundantly expressed in this cell type. Blocking class I HDAC activity with a highly selective inhibitor, MS-275, induced global histone H3 hyperacetylation, reduced RPTC proliferation, and diminished expression of cyclin D1 and proliferating cell nuclear antigen. Silencing HDAC1, 3, or 8 with small interfering RNA resulted in similar biological effects. Activation of epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription 3 (STAT3) was required for RPTC proliferation, and STAT3 functioned downstream of EGFR. Treatment with MS-275 or knockdown of HDAC1, 3, or 8 suppressed EGFR expression and phosphorylation, and silencing HDAC1 and 3 also reduced STAT3 phosphorylation. However, HDAC2 downregulation did not affect RPTC proliferation and phosphorylation of EGFR and STAT3. Collectively, these data reveal a critical role of class I HDACs in mediating proliferation of renal epithelial cells through activation of the EGFR/STAT3 signaling pathway.
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Yan
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.forename: Haidong
authors.initials: H
authors.lastname: Yan
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology; D005455:Fluorescent Antibody Technique; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: D001549:Benzamides; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C118739:entinostat; D066246:ErbB Receptors; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
keywords: class I histone deacetylases; epidermal growth factor receptor; proliferation; renal epithelial cells; signal transducers and activators of transcription 3