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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 …