Functional characterization of ADP ribosyl cyclase signaling pathways in the renal microcirculation Public Deposited

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  • March 21, 2019
  • Thai, Tiffany L.
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Due to its role in the regulation of salt and water balance, the kidney is thought to be the primary organ involved in arterial blood pressure regulation. The mechanisms governing contraction of renal resistance arteries/arterioles are incompletely understood, however. The purpose of my dissertation was to investigate the importance of a novel signaling pathway involving the enzyme ADP ribosyl (ADPR) cyclase in the regulation of calcium (Ca2+) signaling in afferent arterioles and regulation of renal vascular resistance. Physiological measurements of renal blood flow (RBF) were performed on anesthetized rats before, during, and after pharmacological blockade of ADPR cyclase and its downstream target, the ryanodine receptors (RyR). Inhibition of ADPR cyclase under basal conditions resulted in a significant increase in RBF, and impairment of ADPR cyclase or RyR function attenuated RBF responses to the vasoconstrictors angiotensin II (Ang II), norepinephrine (NE), and endothelin-1 (ET-1) by 30-50%. Further analysis revealed that ADPR cyclase and RyR contribute to vasoconstrictor responses induced by either ET receptor, ETA or ETB. Measurements of cytosolic Ca2+ concentration ([Ca2+]i) in isolated rat afferent arterioles revealed that the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) participated in the actions of NE and ET-1. [Ca2+]i transients produced by either agonist were diminished by at least 50% in the presence of disruption of lysosomal Ca2+ or NAADP receptor inhibition. Real time quantitative RT-PCR studies on isolated mouse preglomerular resistance arterioles determined mRNA expression of ADPR cyclase family members CD38 and CD157. Genetic knockout of CD38 resulted in attenuated RBF responses to Ang II, NE, and ET-1. Pharmacological blockade of ADPR in CD38-/- animals resulted in no significant attenuation of Ang II-induced renal vasoconstriction, suggesting that CD38 functions as the predominant ADPR cyclase. Overall, these studies provide evidence for the physiological function of ADPR cyclase, its second messengers, and downstream effectors in the regulation of renal hemodynamics. Further investigation of this pathway in the renal vasculature will result in a deeper understanding of renal hemodynamics.
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  • Arendshorst, William J.
  • Open access

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