Polycystins play a key role in the modulation of cholangiocyte proliferation

BackgroundPolycystin-1 and -2 (PC-1 and PC-2) are critical components of primary cilia, which act as mechanosensors and drive cell response to injury. PC-1 activation involves the cleavage/processing of PC-1 cytoplasmic tail, driven by regulated intramembrane proteolysis or ubiquitine/proteasome, translocation in the nucleus and activation of transcription factors. Mutations of PC-1 or PC-2 occur in polycystic liver where cholangiocyte proliferation is enhanced.AimWe evaluated the involvement of PC-1 and PC-2 in modulating cholangiocyte proliferation.MethodsWe investigated rat cholangiocytes induced to proliferate by 17β-oestradiol. Proliferation was evaluated by PCNA immunoblotting or [3H]-thymidine incorporation into DNA. PC-1 silencing was performed by siRNA, while inhibition of regulated intramembrane proteolysis or proteasome by γ-secretase inhibitor, leupeptin or MG115.ResultsCholangiocyte proliferation was associated with decreased PC-1 and PC-2 expression, which was inversely correlated with enhanced PCNA. The selective silencing of PC-1 induced activation of cholangiocyte proliferation in association with decreased PC-1 expression. Two different regulated intramembrane proteolysis inhibitors, γ-secretase-inhibitor and leupeptin, and the proteasome inhibitor, MG115, abolished the 17β-oestradiol proliferative effect.ConclusionsPC-1 and PC-2 play a major role as modulators of cholangiocyte proliferation suggesting that primary cilia may act as sensors of cell injury driving, when activated, a proliferative cholangiocyte response to trigger the reparative processes.