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Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease.

Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2+ channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knock-out mice. In proximal tubule-derived, PC1-knock-out cells, adenylyl cyclase 6 and 3 (AC6 and -3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared with control cells containing PC1. Intracellular Ca2+ was higher in PC1-knock-out cells than in control cells. HDAC inhibition caused a drop in intracellular Ca2+ and increased ATP-simulated Ca2+ release. HDAC6 inhibition reduced the release of Ca2+ from the endoplasmic reticulum induced by thapsigargin, an inhibitor of endoplasmic reticulum Ca2+-ATPase. HDAC6 inhibition and treatment of cells with the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) reduced cAMP levels in PC1-knock-out cells. Finally, the calmodulin inhibitors W-7 and W-13 reduced cAMP levels, and W-7 reduced cyst growth, suggesting that AC3 is involved in cyst growth regulated by HDAC6. We conclude that HDAC6 inhibition reduces cell growth primarily by reducing intracellular cAMP and Ca2+ levels. Our results provide potential therapeutic targets that may be useful as treatments for ADPKD.
AuthorsMurali K Yanda, Qiangni Liu, Valeriu Cebotaru, William B Guggino, Liudmila Cebotaru
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 43 Pg. 17897-17908 (10 27 2017) ISSN: 1083-351X [Electronic] United States
PMID28887310 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • Calcium Chelating Agents
  • Histone Deacetylase Inhibitors
  • TRPP Cation Channels
  • polycystic kidney disease 2 protein
  • Thapsigargin
  • Cyclic AMP
  • protein kinase D
  • Protein Kinase C
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases
  • Calcium
Topics
  • Animals
  • Calcium (metabolism)
  • Calcium Chelating Agents (pharmacology)
  • Calcium Signaling (drug effects, genetics)
  • Cell Line
  • Cyclic AMP (genetics, metabolism)
  • Cysts (enzymology, genetics, pathology)
  • Disease Models, Animal
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors (pharmacokinetics)
  • Histone Deacetylases (genetics, metabolism)
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Polycystic Kidney, Autosomal Dominant (enzymology, genetics, pathology)
  • Protein Kinase C (genetics, metabolism)
  • TRPP Cation Channels (genetics, metabolism)
  • Thapsigargin (pharmacology)

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