title: Treatment with a selective histone deacetylase 6 inhibitor decreases lupus nephritis in NZB/W mice.
abstract: To date, there are 18 histone deacetylase (HDAC) enzymes, divided into four classes, which alter protein function by removing acetyl groups from lysine residues. Prior studies report that non-selective HDAC inhibitors decrease disease in lupus mouse models. Concern for adverse side effects of non-selective HDAC inhibition supports investigation of selective-HDAC inhibition. We hypothesized that a selective HDAC-6 inhibitor (HDAC6i) will alleviate disease in a mouse model of lupus by increasing acetylation of alpha-tubulin. Intraperitoneal injections of the selective HDAC6i ACY-1083 (0.3 mg/kg, 1 mg/kg, or 3 mg/kg), vehicle control, or dexamethasone were administered to 21-week-old, female NZB/W mice, 5 days a week, for 13 weeks. Disease progression was evaluated by proteinuria, serum levels of anti-dsDNA antibody, cytokines and immunoglobulins, and post mortem evaluation of nephritis and T cell populations in the spleen. HDAC6i treatment decreased proteinuria, glomerular histopathology, IgG, and C3 scores when compared to vehicle-treated mice. Within glomeruli of HDAC6i-treated mice, there was increased acetylation of alpha-tubulin and decreased NF-κB. Additionally, HDAC6i decreased serum IL-12/IL-23 and Th17 cells in the spleen. Taken together, these results suggest HDAC-6 inhibition may decrease lupus nephritis in NZB/W mice via mechanisms involving acetylation of alpha-tubulin and decreased NF-κB in glomeruli as well as inhibition of Th17 cells.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Vieson
authors.affiliation: Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Gojmerac
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
authors.forename: Deena
authors.initials: D
authors.lastname: Khan
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
authors.forename: Rujuan
authors.initials: R
authors.lastname: Dai
authors.affiliation: Acetylon Pharmaceuticals, Boston, MA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: van Duzer
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winton-Salem, NC, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
authors.forename: Xin M
authors.initials: XM
authors.lastname: Luo
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA. chreilly@vcom.vt.edu.|Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D005260:Female; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes; D008181:Lupus Nephritis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D014404:Tubulin / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D014404:Tubulin; D000073864:Histone Deacetylase 6