title: Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease.
abstract: Abnormal proliferation of cyst-lining epithelium and increased intracystic fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) are thought to contribute to cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Histone deacetylase 6 (HDAC6) expression and activity are increased in certain cancers, neurodegenerative diseases, and in Pkd1-mutant renal epithelial cells. Inhibition of HDAC6 activity with specific inhibitors slows cancer growth. Here we studied the effect of tubacin, a specific HDAC6 inhibitor, on cyst growth in polycystic kidney disease. Treatment with tubacin prevented cyst formation in MDCK cells, an in vitro model of cystogenesis. Cyclic AMP stimulates cell proliferation and activates intracystic CFTR-mediated chloride secretion in ADPKD. Treatment with tubacin downregulated cyclic AMP levels, inhibited cell proliferation, and inhibited cyclic AMP-activated CFTR chloride currents in MDCK cells. We also found that tubacin reduced cyst growth by inhibiting proliferation of cyst-lining epithelial cells, downregulated cyclic AMP levels, and improved renal function in a Pkd1-conditional mouse model of ADPKD. Thus, HDAC6 could play a role in cyst formation and could serve as a potential therapeutic target in ADPKD.
authors.affiliation: Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Qiangni
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Yanda
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Clement
authors.initials: C
authors.lastname: Boinot
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Outeda
authors.affiliation: Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Watnick
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: vcebotaru@medicine.umaryland.edu.
authors.forename: Valeriu
authors.initials: V
authors.lastname: Cebotaru
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002712:Chlorides / Q000097:blood / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000235:genetics
chemical_list: D000813:Anilides; D002712:Chlorides; D000242:Cyclic AMP; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D050396:TRPP Cation Channels; C474316:tubacin; C499033:Hdac6 protein, mouse
keywords: autosomal dominant polycystic kidney disease; cyclic AMP; histone deacetylase 6 inhibitor; renal cyst growth