Background
Histone deacetylase inhibitors (HDACi) have therapeutic effects on various models of renal diseases including autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanism is unclear. Objectives: Here, we studied the role of trichostatin A (TSA), a specific HDACi, in regulating cyst growth to test the possibility that HDACi might help manage ADPKD by enhancing autophagy.
Conclusions
Our results suggest that HDACi may prevent cyst formation by activation of the AMPK pathway and autophagy. They also imply that HDACi could have therapeutic potential for ADPKD treatment.
Results
Autophagy protein expression was higher in cultured Pkd1 knockout (Pkd1-/-) cells, an in vitro model of cystogenesis, compared with control cells. TSA prevented cyst formation in Pkd1-/- cells. We further tested whether TSA could not reduce the size of an already established cyst after inhibition of autophagy by chloroquine in Pkd1-/- cells. In vivo, treatment with TSA significantly slowed cyst growth in Pkd1-/- mice. Moreover, TSA treatment stimulated AMPK and inactivated mTOR during cyst growth in Pkd1-/- cells and kidneys in mice. Conclusions: Our results suggest that HDACi may prevent cyst formation by activation of the AMPK pathway and autophagy. They also imply that HDACi could have therapeutic potential for ADPKD treatment.