Regulation of renin release via cyclic ADP-ribose-mediated signaling: evidence from mice lacking CD38 gene.
OBJECTIVE
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 (UNaV) more significantly decreased in CD38(-/-) than CD38(+/+) mice. Similarly, more increases in PRA but more decreases in GFR, RBF, UV and UNaV were observed in CD38(-/-) than CD38(+/+) mice when they had a low renal perfusion pressure (RPP).


CONCLUSIONS
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.
Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
Jing
J
Xiong
Min
M
Xia
Fan
F
Yi
Justine M
JM
Abais
Ningjun
N
Li
Krishna M
KM
Boini
Pin-Lan
PL
Li
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D012083:Renin; D007545:Isoproterenol