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.