Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 313, Issue 4, Pages F997-F1004Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00186.2017
Keywords
autosomal-dominant polycystic kidney disease; renal cyst growth; histone deacetylase 6 inhibitor; adenosine 3 ',5 '-cyclic monophosphate; poly-cystic kidney disease
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [P30-DK-079310]
- NIDDK [P30-DK-090868]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK079310, P30DK090868] Funding Source: NIH RePORTER
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Adult onset autosomal-dominant polycystic kidney disease ( ADPKD) is caused by mutations in either the PKD1 or PKD2 gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in PKD1 mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 wk after knockout of polycystin 1 function. It also prevented cyst formation in MDCK.2 cells, an in vitro model of cystogenesis, and in an ADPKD cell line derived from the proximal tubules from a pkd1(-/-) mouse ( PN cells). In PN cells ACY-1215 also reduced the size of already established cysts. We found that ACY-1215 lowered cAMP levels and protein expression of adenylyl cyclase 6. Our results suggest that HDAC6 could potentially serve as a therapeutic target in ADPKD.
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