Aquaporin 11-Dependent Inhibition of Proliferation by Deuterium Oxide in Activated Hepatic Stellate Cells.

Deuterium oxide (D₂O) has been reported to be active toward various in vitro cell lines in combination with phytochemicals. Our objective was to describe, for the first time, the effect of D₂O on the proliferation of hepatic stellate cells (HSCs). After D₂O treatment, the p53-cyclin-dependent kinase (CDK) pathway was stimulated, leading to inhibition of the proliferation of HSCs and an increase in the [ATP]/[ADP] ratio. We also evaluated the role of aquaporin (AQP) 11 in activated HSCs. We found that D₂O treatment decreased AQP11 expression levels. Of note, AQP11 levels elevated by a genetic approach counteracted the D₂O-mediated inhibition of proliferation. In addition, the expression levels of AQP11 negatively correlated with those of p53. On the other hand, cells transfected with an AQP11-targeted small interfering RNA (siRNA) showed enhanced inhibition of proliferation. These findings suggest that the inhibition of cell proliferation by D₂O in activated HSCs could be AQP11 dependent. Our previous studies have documented that bisdemethoxycurcumin (BDMC) induces apoptosis by regulating heme oxygenase (HO)-1 protein expression in activated HSCs. In the current study, we tested whether cotreatment with BDMC and D₂O can modulate the AQP11-dependent inhibition of cell proliferation effectively. We observed that D₂O cotreatment with BDMC significantly decreased cell proliferation compared to treatment with D₂O alone, and this effect was accompanied by downregulation of HO-1 and an increase in p53 levels.