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

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    Author
    Yanda, M.K.
    Liu, Q.
    Cebotaru, V.
    Date
    2017
    Journal
    Journal of Biological Chemistry
    Publisher
    American Society for Biochemistry and Molecular Biology Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1074/jbc.M117.803775
    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.
    Sponsors
    These studies utilized resources provided by the NIDDK-sponsored Baltimore Polycystic Kidney Disease Research and Clinical Core Center (Grant P30 DK090868).
    Keyword
    Calcium--metabolism
    Calcium Signaling--drug effects
    Cyclic AMP--metabolism
    Histone Deacetylase Inhibitors--pharmacokinetics
    Histone Deacetylases--metabolism
    Polycystic Kidney, Autosomal Dominant--enzymology
    Mice, Knockout
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85032503470&doi=10.1074%2fjbc.M117.803775&partnerID=40&md5=15e0e929975fe7a094fe833eca3e6391; http://hdl.handle.net/10713/11347
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M117.803775
    Scopus Count
    Collections
    UMB Open Access Articles 2017

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