Histone deacetylase 6 Inhibition reduces cysts by decreasing via cAMP and Ca2+ in knockout mouse models of polycystic kidney disease [Signal Transduction]

Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive en-largement of multiple renal cysts, often leading to renal failure which cannot be prevented by an 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 in-hibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knockout mice. In proximal tubule-derived, PC1 knockout cells, adenylyl cyclase 6 and 3 (AC6 & 3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared to control cells containing PC1. Intracellular Ca2+ was higher in PC1-knockout 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 ER in-duced by thapsigargin, an inhibitor of the endoplasmic reticulum, Ca2+-ATPase. HDAC6 inhibi-tion and treating cells with the intracellular Ca2+ chelator BAPTA-AM reduced cAMP levels in PC1 knockout cells. Finally, the calmodulin inhibitors, W7 and W13, reduced cAMP levels and W7 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.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2wfgKri
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