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The present study was designed to test the hypothesis that cyclic-ADP-ribose (cADPR) serves as a novel second messenger to mediate intracellular Ca(2+) concentration in As4.1 cells, a prototype of renal juxtaglomerular cells, and thereby regulates the renin production and release. Western blot analysis showed that CD38, an enzyme responsible for the production of cADPR, was abundant in As4.1 cells. Using cADPR cycling assay, it was found that NaCl stimulated cADPR production in these cells, which was blocked by inhibition of ADP-ribosyl cyclase with nicotinamide. HPLC analysis showed that the conversion rate of beta-NGD into cGDPR was dramatically increased by NaCl, which was attenuated by nicotinamide. Using fluorescent microscopic imaging analysis, NaCl (100 mM) was demonstrated to stimulate a rapid Ca(2+) increase from the endoplasmic reticulum (ER), which was inhibited by a cADPR antagonist, 8-bromo-cADPR (30 microM), an inhibitor of ADP-ribosyl cyclase, nicotinamide (6 mM), the ryanodine receptors blocker, ryanodine (30 microM), or a Ca(2+)-induced Ca(2+) release inhibitor, tetracaine (10 microM) by 70-90%. Finally, NaCl was found to significantly lower the renin production and release levels in As4.1 cells, which was accompanied by decreases in renin mRNA levels. Pretreatment of these cells with various inhibitors or blockers above significantly blocked the inhibitory effect of NaCl on renin production and release. These results indicate that cADPR-mediated Ca(2+) signaling pathway is present in As4.1 cells and that this signaling pathway may play a contributing role in the regulation of renin production and release.

Role of Cyclic ADP-Ribose-Ca<sup>2+</sup> Signaling in Mediating Renin Production and Release in As4.1 Cells