Regulation of renin release via cyclic adp-ribose-mediated signaling: Evidence from mice lacking CD38 gene

Background/Aims: Despite extensive studies, the intracellular regulatory mechanism of renin production and release is still poorly understood. The present study was designed to test whether CD38-ADP-ribosylcyclase signaling pathway contributes to the regulation of renin production and release, and to examine whether CD38 gene knockout (CD38 ^-/- ) can change this important renal endocrinal function. Methods: ADP-ribosylcyclase activity was estimated utilizing HPLC, cADPR levels from western blot, plasma renin activity from RIA kit, urinary sodium and potassium excretion from fame photometry. Results: The expression of CD38 and the activity of ADP-ribosylcyclase to produce cyclic ADP-ribose (cADPR) were nearly abolished in the kidney from CD38 ^-/- mice, indicating that CD38 gene is a major enzyme responsible for the generation of cADPR in vivo. Mice lacking CD38 gene showed increased plasma renin activity (PRA) in either conscious or anesthetized status (P<0.05). Low salt intake significantly increased, but high salt intake significantly decreased renin release in both CD38 ^+/+ and CD38 ^-/- mice. In acute experiments, it was demonstrated that plasma renin activity (PRA) significantly increased upon isoprenaline infusion in CD38 ^-/- mice compared to CD38 ^+/+ mice. Accompanied with such increase in PRA, glomerular filtration rate (GFR), renal blood flow (RBF), urine volume (UV) and sodium excretion (U _Na V) more significantly decreased in CD38 ^-/- than CD38 ^+/+ mice. Similarly, more increases in PRA but more decreases in GFR, RBF, UV and U _Na V were observed in CD38 ^-/- than CD38 ^+/+ mice when they had a low renal perfusion pressure (RPP). Conclusion: CD38-cADPR-mediated signaling may importantly contribute to the maintenance of low PRA and participate in the regulation of renal hemodynamics and excretory function in mice.