期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 294, 期 4, 页码 F982-F989出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00483.2007
关键词
cyclic ADP-ribose; intracellular Ca2+ concentration
Molecular mechanism of ADP-ribosyl cyclase activation in angiotensin II signaling in murine mesangial cells. Am J Physiol Renal Physiol 294: F982-F989, 2008. First published February 13, 2008; doi:10.1152/ajprenal.00483.2007. -ADP- ribosyl cyclase (ADPR-cyclase) produces a Ca2+-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 Ca2+ concentrations through a transient Ca2+ release via an inositol 1,4,5-trisphosphate receptor and a sustained Ca2+ influx via L-type Ca2+ channels. The sustained Ca2+ signal, but not the transient Ca2+ 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-gamma 1. 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 [H-3] thymidine and [H-3] 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.
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