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dc.contributor.authorYanda, M.K.
dc.contributor.authorLiu, Q.
dc.contributor.authorCebotaru, V.
dc.date.accessioned2019-11-01T12:49:40Z
dc.date.available2019-11-01T12:49:40Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85032503470&doi=10.1074%2fjbc.M117.803775&partnerID=40&md5=15e0e929975fe7a094fe833eca3e6391
dc.identifier.urihttp://hdl.handle.net/10713/11347
dc.description.abstractAutosomal 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.en_US
dc.description.sponsorshipThese studies utilized resources provided by the NIDDK-sponsored Baltimore Polycystic Kidney Disease Research and Clinical Core Center (Grant P30 DK090868).en_US
dc.description.urihttps://doi.org/10.1074/jbc.M117.803775en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.en_US
dc.relation.ispartofJournal of Biological Chemistry
dc.subject.meshCalcium--metabolismen_US
dc.subject.meshCalcium Signaling--drug effectsen_US
dc.subject.meshCyclic AMP--metabolismen_US
dc.subject.meshHistone Deacetylase Inhibitors--pharmacokineticsen_US
dc.subject.meshHistone Deacetylases--metabolismen_US
dc.subject.meshPolycystic Kidney, Autosomal Dominant--enzymologyen_US
dc.subject.meshMice, Knockouten_US
dc.titleHistone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2 in knock-out mouse models of polycystic kidney diseaseen_US
dc.typeArticleen_US
dc.identifier.doi10.1074/jbc.M117.803775
dc.identifier.pmid28887310


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