CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: Attenuation of hepatic fibrosis by CD38 ablation

Abstract

CD38 is a type II glycoprotein that is responsible for the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), Ca2+-mobilizing second messengers. The activation of hepatic stellate cells (HSCs) is a critical event in hepatic fibrosis because these cells are the main producers of extracellular matrix proteins in the liver. Recent evidence indicates that the renin-angiotensin system plays a major role in liver fibrosis. In this study, we showed that angiotensin II (Ang II) evoked long lasting Ca2+ rises and induced NAADP or cADPR productions via CD38 in HSCs. Inositol 1,4,5-trisphosphate as well as NAADP-induced initial Ca2+ transients were prerequisite for the production of cADPR, which was responsible for later sustained Ca2+ rises in the Ang II-treated HSCs. Ang II-mediated inositol 1,4,5-trisphosphate- and NAADP-stimulated Ca2+ signals cross-talked in a dependent manner with each other. We also demonstrated that CD38 plays an important role in Ang II-induced proliferation and overproduction of extracellular matrix proteins in HSCs, which were reduced by an antagonistic cADPR analog, 8-bromo-cADPR, or in CD38-/- HSCs. Moreover, we presented evidence to implicate CD38 in the bile duct ligation-induced liver fibrogenesis; infiltration of inflammatory cells and expressions of γ-smooth muscle actin, transforming growth factor-β1, collagen αI(1), and fibronectin were reduced in CD38-/- mice compared with those in CD38-/- mice. These results demonstrate that CD38-mediated Ca2+ signals contribute to liver fibrosis via HSCs activation, suggesting that intervention of CD38 activation may help prevent hepatic fibrosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.