CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: attenuation of hepatic fibrosis by CD38 ablation.
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), Ca(2+)-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 Ca(2+) rises and induced NAADP or cADPR productions via CD38 in HSCs. Inositol 1,4,5-trisphosphate as well as NAADP-induced initial Ca(2+) transients were prerequisite for the production of cADPR, which was responsible for later sustained Ca(2+) rises in the Ang II-treated HSCs. Ang II-mediated inositol 1,4,5-trisphosphate- and NAADP-stimulated Ca(2+) 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 alpha-smooth muscle actin, transforming growth factor-beta1, collagen alphaI(1), and fibronectin were reduced in CD38(-/-) mice compared with those in CD38(+/+) mice. These results demonstrate that CD38-mediated Ca(2+) signals contribute to liver fibrosis via HSCs activation, suggesting that intervention of CD38 activation may help prevent hepatic fibrosis.
Kim
Seon-Young
SY
Department of Biochemistry, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea.
Cho
Baik Hwan
BH
Kim
Uh-Hyun
UH
D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency* / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D017353:Gene Deletion; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008954:Models, Biological; D009249:NADP / Q000031:analogs & derivatives / Q000096:biosynthesis
D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D000804:Angiotensin II; D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D015544:Inositol 1,4,5-Trisphosphate; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium