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

Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA.
Cellular Physiology and Biochemistry (Impact Factor: 2.88). 01/2013; 31(1):44-55. DOI: 10.1159/000343348
Source: PubMed


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.

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Available from: Jing Xiong, Sep 16, 2014
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    • ", and its role as a substrate for NAD-dependent sirtuin deacetylases (Escande et al. 2013) (Fig. 1). Both signalling pathways have been associated with cellular mechanisms of ageing, metabolic function, transcriptional regulation, cellular stress resistance mechanisms and cell death (Moss et al. 2013; Nipp et al. 2013; Quarona et al. 2013; Sobko et al. 2013; Xiong et al. 2013; Xu et al. 2013). Numerous studies have postulated the potential role of CD38, a type II membrane protein, as the major NADase in mammalian cells. "
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    ABSTRACT: Over the last decade, the importance of NAD(+) has expanded beyond its role as an essential cofactor for energy metabolism. NAD(+) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD(+) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD(+) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD(+) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD(+) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD(+) and ATP levels and SIRT1 function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD(+) catabolism, our discovery of CD38 as the major regulator of cellular NAD(+) levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.
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    • "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. "
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