title: Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.
abstract: Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Yanli
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Haidong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005492:Folic Acid / Q000009:adverse effects; D006655:Histone Deacetylases / Q000145:classification / Q000502:physiology*; D007527:Isoenzymes / Q000145:classification / Q000502:physiology; D007668:Kidney / Q000473:pathology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D012206:Rhabdomyolysis / Q000150:complications; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D005492:Folic Acid; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases
keywords: acute kidney injury; dedifferentiation; epidermal growth factor receptor; histone deacetylases; proliferation