CD38 ADP ribosyl (ADPR) cyclase is a membrane-bound enzyme that produces metabolites known to promote Ca2+ mobilization mediated by ryanodine receptors (RyR) in arteriolar smooth muscle cells. We posit that renal CD38 is central to the development of angiotensin II (Ang II)-induced hypertension (AIH) and that CD38-deficient mice exhibit less pronounced renal vasoconstriction, Na+ retention and AIH than do wild-type (WT) mice.
AIM 1 tests the hypothesis that CD38 ADPR cyclase participates in the development of AIH such that Ang II produces less pronounced hypertension in CD38-/- (global genetic deficiency) vs. WT mice. Less severe hypertension is also predicted in WT mice with targeted, renal-specific partial knockdown of CD38 induced by siRNA. The severity of AIH is determined by measuring 24-hr arterial pressure (telemetry) in conscious, unrestrained mice before and during chronic Ang II infusion. Also measured are 24 hr urinary excretion of nitrite/nitrate and 8-iso-PGF2? to assess nitric oxide (NO) production and oxidative stress. CD38 mRNA and ADPR cyclase activity will be quantified in preglomerular vessels.
AIM 2 assesses the contribution of CD38 ADPR cyclase to renal vasoconstriction and the rightward shift in the pressure-natriuresis relation in AIH. We predict that the kidneys of CD38-deficient mice excrete Na+ more rapidly in response to an acute salt load than WT mice during development of AIH, with excretion rates becoming similar in established AIH. Conscious and anesthetized mice with global knockout and renal-specific knockdown of CD38 will be evaluated in both phases.
AIM 3 evaluates the hypothesis that CD38 is the major ADPR cyclase mediating G- protein coupled receptor-elicited Ca2+ signaling involving RyR and Ca2+-induced Ca2+ release in isolated afferent arterioles and renal vasoconstriction in vivo. We predict that Ca2+ signaling and vascular responsiveness to vasoconstrictor agents (Ang II, ET-1, TxA2) are attenuated in CD38-deficient vs. WT mice during control and AIH conditions. Scatchard analysis of radioligand binding will characterize Ang II, ET-1, and TP receptor affinity and/or density in renal microvessels. Our goal is to identify a sequence of events that precede or occur early during the development of hypertension and thus are more likely to be causative than secondary, pressure-dependent consequences. Combining gene-targeted deletion of CD38, global and renal- specific, with pharmacological inhibition of ADPR cyclase and RyR-mediated Ca2+ release will provide important new information that CD38 is the primary cyclase family member mediating Ca2+ signaling in the renal microcirculation and its functional significance in long-term regulation of renal vasoconstriction, Na+ retention and the development of AIH. Successful completion of our novel studies of this underappreciated pathway will significantly advance our understanding of cellular/molecular mechanisms of Ca2+ signaling in the renal microcirculation and regulation of renal vascular reactivity in health and disease, making a major impact on the field.

Public Health Relevance

More than 70 million Americans have hypertension, a major cardiovascular risk factor, highly predictive of other vascular diseases such as atherosclerosis, diabetes mellitus, renal failure, and stroke. Studies are proposed to investigate mechanisms regulating calcium metabolism in smooth muscle cells that contract blood vessels. Abnormal cell signaling can cause arteries to be hyper-responsive to vasoactive hormones and cause the kidneys to retain inappropriate amounts of salt and water, resulting in an expanded blood volume and the development of high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL002334-56
Application #
8383467
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
1986-09-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
56
Fiscal Year
2013
Total Cost
$560,599
Indirect Cost
$181,816
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Yu, Hao; Yang, Tao; Gao, Peng et al. (2016) Caffeine intake antagonizes salt sensitive hypertension through improvement of renal sodium handling. Sci Rep 6:25746
Carlström, Mattias; Wilcox, Christopher S; Arendshorst, William J (2015) Renal autoregulation in health and disease. Physiol Rev 95:405-511
Vogel, Paul A; Yang, Xi; Moss, Nicholas G et al. (2015) Superoxide enhances Ca2+ entry through L-type channels in the renal afferent arteriole. Hypertension 66:374-81
Trott, Daniel W; Thabet, Salim R; Kirabo, Annet et al. (2014) Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64:1108-15
Moss, Nicholas G; Kopple, Tayler E; Arendshorst, William J (2014) Renal vasoconstriction by vasopressin V1a receptors is modulated by nitric oxide, prostanoids, and superoxide but not the ADP ribosyl cyclase CD38. Am J Physiol Renal Physiol 306:F1143-54
Li, Li; Wang, Fei; Wei, Xing et al. (2014) Transient receptor potential vanilloid 1 activation by dietary capsaicin promotes urinary sodium excretion by inhibiting epithelial sodium channel α subunit-mediated sodium reabsorption. Hypertension 64:397-404
Moss, Nicholas G; Vogel, Paul A; Kopple, Tayler E et al. (2013) Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion. Am J Physiol Renal Physiol 305:F830-8
Liu, Ying; Echtermeyer, Frank; Thilo, Florian et al. (2012) The proteoglycan syndecan 4 regulates transient receptor potential canonical 6 channels via RhoA/Rho-associated protein kinase signaling. Arterioscler Thromb Vasc Biol 32:378-85
Arendshorst, William J (2012) Connexin 40 mediates tubuloglomerular feedback paracrine signaling by coupling tubular and vascular cells in the renal juxtaglomerular apparatus. Am J Physiol Renal Physiol 303:F1409-11
Kogan, Paul; Johnson, Kennita A; Feingold, Steven et al. (2011) Validation of dynamic contrast-enhanced ultrasound in rodent kidneys as an absolute quantitative method for measuring blood perfusion. Ultrasound Med Biol 37:900-8

Showing the most recent 10 out of 17 publications