title: Molecular mechanism of ADP-ribosyl cyclase activation in angiotensin II signaling in murine mesangial cells.
abstract: ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca(2+)-mobilizing second messenger cyclic ADP-ribose (cADPR) from NAD(+). In this study, we investigated the molecular basis of ADPR-cyclase activation and the following cellular events in angiotensin II (ANG II) signaling in mouse mesangial cells (MMCs). Treatment of MMCs with ANG II induced an increase in intracellular Ca(2+) concentrations through a transient Ca(2+) release via an inositol 1,4,5-trisphosphate receptor and a sustained Ca(2+) influx via L-type Ca(2+) channels. The sustained Ca(2+) signal, but not the transient Ca(2+) signal, was blocked by a cADPR antagonistic analog, 8-bromo-cADPR (8-Br-cADPR), and an ADPR-cyclase inhibitor, 4,4'-dihydroxyazobenzene (DHAB). In support of the results, ANG II stimulated cADPR production in a time-dependent manner, and DHAB inhibited ANG II-induced cADPR production. Application of pharmacological inhibitors revealed that activation of ADPR-cyclase by ANG II involved ANG II type 1 receptor, phosphoinositide 3-kinase, protein tyrosine kinase, and phospolipase C-gamma1. Moreover, DHAB as well as 8-Br-cADPR abrogated ANG II-mediated Akt phosphorylation, nuclear translocation of nuclear factor of activated T cell, and uptake of [(3)H]thymidine and [(3)H]leucine in MMCs. These results demonstrate that ADPR-cyclase in MMCs plays a pivotal role in ANG II signaling for cell proliferation and protein synthesis.
authors.affiliation: Dept. of Biochemistry, Chonbuk National Univ. Medical School, Keum-am dong, Jeonju, 561-182, Republic of Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Gul
authors.forename: So-Young
authors.initials: SY
authors.lastname: Rah
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
authors.forename: Mie-Jae
authors.initials: MJ
authors.lastname: Im
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D011725:Pyridines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D036563:Cyclic ADP-Ribose; C073402:PD 123319; D036541:ADP-ribosyl Cyclase; D002118:Calcium