Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury

• Published in: American journal of physiology. Renal physiology Vol. 305; no. 1; pp. F61 - F70
• Main Authors: Kim, Jee In, Jung, Kyong-Jin, Jang, Hee-Seong, Park, Kwon Moo
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2013
• Subjects: Acetylation; Animals; Binding Sites; Cell Line; Chromatin; Chromatin Immunoprecipitation; Dihydrotestosterone - pharmacology; Disease Models, Animal; Female; Gender; Gene expression; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones - metabolism; Ischemia; Kidney - blood supply; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Kidney diseases; Lipopolysaccharides - pharmacology; Macrophages - enzymology; Male; Mice; Mice, Inbred C57BL; Orchiectomy; Ovariectomy; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Promoter Regions, Genetic; Reperfusion Injury - enzymology; Reperfusion Injury - genetics; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; RNA Interference; Rodents; Serine Proteinase Inhibitors - pharmacology; Sex Factors; Testosterone; Time Factors; Transfection; PAI-1; kidney ischemia and reperfusion; gender dimorphism; HDAC11
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00015.2013

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.