title: Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury.
abstract: Male gender and the male hormone testosterone increase susceptibility to kidney ischemia and reperfusion (I/R) injury, which is associated with inflammatory responses. Possible involvement of histone deacetylase (HDAC) in inflammatory responses has been suggested. We investigated the gender-specific role of HDACs in plasminogen activator inhibitor type-1 (PAI-1) expression and I/R injury. PAI-1 inhibition protected the kidney from I/R-induced inflammation and functional loss. Among HDACs, only HDAC11 negatively regulated PAI-1 expression in I/R-subjected kidney gender specifically and lipopolysaccharide (LPS)-stimulated mouse monocytes/macrophages. HDAC11 gene silencing increased PAI-1 expression. Chromatin immunoprecipitation assay confirmed binding of HDAC11 to the promoter region of PAI-1 and then release by I/R insult or LPS treatment. I/R-induced HDAC11 release was inhibited by orchiectomy and reversed by dihydrotestosterone treatment. Release of HDAC11 increased acetylation of histone H3. In conclusion, male gender and male hormones accelerate I/R-induced decreases in expression and binding of HDAC11, resulting in an increase in PAI-1 expression. These data provide important insight into gender dimorphism offering HDAC11 as a novel target for I/R injury.
authors: Department of Anatomy and BK21, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors: Jee In
authors: JI
authors: Kim
authors: Kyong-Jin
authors: KJ
authors: Jung
authors: Hee-Seong
authors: HS
authors: Jang
authors: Kwon Moo
authors: KM
authors: Park
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D013196:Dihydrotestosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D010052:Ovariectomy; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012737:Sex Factors; D013997:Time Factors; D014162:Transfection
chemical_list: D006657:Histones; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D013196:Dihydrotestosterone; C462506:HDAC11 protein, human; D006655:Histone Deacetylases
keywords: HDAC11; PAI-1; gender dimorphism; kidney ischemia and reperfusion