TY - JOUR
T1 - An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease
AU - Yanda, Murali K.
AU - Liu, Qiangni
AU - Cebotaru, Liudmila
N1 - Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/10
Y1 - 2017/10
N2 - Adultonset 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.
AB - Adultonset 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.
KW - Adenosine 3′, 5′-cyclic monophosphate
KW - Autosomal-dominant polycystic kidney disease
KW - Histone deacetylase 6 inhibitor
KW - Polycystic kidney disease
KW - Renal cyst growth
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U2 - 10.1152/ajprenal.00186.2017
DO - 10.1152/ajprenal.00186.2017
M3 - Article
C2 - 28747357
AN - SCOPUS:85030547279
VL - 313
SP - F997-F1004
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
SN - 0363-6127
IS - 4
ER -