An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease

Murali K. Yanda, Qiangni Liu, Liudmila Cebotaru

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F997-F1004
JournalAmerican Journal of Physiology - Renal Physiology
Volume313
Issue number4
DOIs
Publication statusPublished - Oct 1 2017

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Keywords

  • Adenosine 3′, 5′-cyclic monophosphate
  • Autosomal-dominant polycystic kidney disease
  • Histone deacetylase 6 inhibitor
  • Polycystic kidney disease
  • Renal cyst growth

ASJC Scopus subject areas

  • Physiology
  • Urology

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