Regulation of Renin Release via Cyclic ADP-Ribose-Mediated Signaling: Evidence from Mice Lacking CD38 Gene

Abstract

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_NaV) more significantly decreased in CD38^-/- than CD38^+/+ mice. Similarly, more increases in PRA but more decreases in GFR, RBF, UV and U_NaV 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.

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Intermittent Hypoxia Upregulates the Renin and Cd38 mRNAs in Renin-Producing Cells via the Downregulation of miR-203

“…In addition, several studies have suggested the regulation of Ren to be controlled by the CD38-cyclic ADP-ribose (cADPR)-mediated signaling pathway [ 5 ]. cADPR serves as a second messenger in terms of controlling the intracellular Ca 2+ concentrations.…”

Roles of NAD+, PARP-1, and Sirtuins in Cell Death, Ischemic Brain Injury, and Synchrotron Radiation X-Ray-Induced Tissue Injury

“…Multiple studies using CD38 knockout mice have suggested that CD38/cADPR system plays important roles in neutrophils death by infection [ 113 ], autoimmune diabetes [ 114 ], and renal hemodynamics and excretory function [ 115 ]. However, there have been only quite limited studies on the roles of CD38/cADPR system in CNS.…”