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: Liudmila Cebotaru, Qiangni Liu, Murali K Yanda, Clement Boinot, Patricia Outeda, David L Huso, Terry Watnick, William B Guggino, Valeriu Cebotaru
• Journal: Kidney international (Kidney Int) Vol. 90 Issue 1 Pg. 90-9 (07 2016) ISSN: 1523-1755 [Electronic] United States
• PMID: 27165822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anilides
• Chlorides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• TRPP Cation Channels
• polycystic kidney disease 1 protein
• tubacin
• Cystic Fibrosis Transmembrane Conductance Regulator
• Cyclic AMP
• Hdac6 protein, mouse
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Anilides (pharmacology)
• Animals
• Cell Proliferation (drug effects)
• Chlorides (blood, metabolism)
• Cyclic AMP (blood)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Disease Models, Animal
• Dogs
• Down-Regulation
• Epithelial Cells (metabolism, physiology)
• Female
• Histone Deacetylase 6
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (genetics, metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Kidney (drug effects, enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Polycystic Kidney, Autosomal Dominant (genetics, metabolism)
• TRPP Cation Channels (genetics)