Calcium signalling from the type I inositol 1,4,5-trisphosphate receptor is required at early phase of liver regeneration

Background & AimsLiver regeneration is a multistage process that unfolds gradually, with different mediators acting at different stages of regeneration. Calcium (Ca2+) signalling is essential for liver regeneration. In hepatocytes, Ca2+ signalling results from the activation of inositol 1,4,5-trisphosphate receptors (InsP(3)R) of which two of the three known isoforms are expressed (InsP(3)R-I and InsP(3)R-II). Here, we investigated the role of the InsP(3)R-I-dependent Ca2+ signals in hepatic proliferation during liver regeneration. MethodsPartial hepatectomy (HX) in combination with knockdown of InsP(3)R-I (AdsiRNA-I) was used to evaluate the role of InsP(3)R-I on liver regeneration and hepatocyte proliferation, as assessed by liver to body mass ratio, PCNA expression, immunoblots and measurements of intracellular Ca2+ signalling. ResultsAdsiRNA-I efficiently infected the liver as demonstrated by the expression of -galactosidase throughout the liver lobules. Moreover, this construct selectively and efficiently reduced the expression of InsP(3)R-I, as evaluated by immunoblots. Expression of AdsiRNA-I in liver decreased peak Ca2+ amplitude induced by vasopressin in isolated hepatocytes 2days after HX. Reduced InsP(3)R-I expression prior to HX also delayed liver regeneration, as measured by liver to body weight ratio, and reduced hepatocyte proliferation, as evaluated by PCNA staining, at the same time point. At later stages of regeneration, control hepatocytes showed a decreased expression of InsP(3)R, as well as reduced InsP(3)R-mediated Ca2+ signalling, events that did not affect liver growth. ConclusionTogether, these results show that InsP(3)R-I-dependent Ca2+ signalling is an early triggering pathway required for liver regeneration.