Histone Deacetylase Inhibitors Reduce Cysts by Activating Autophagy in Polycystic Kidney Disease

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. 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.