Mice lacking the ADP ribosyl cyclase CD38 exhibit attenuated renal vasoconstriction to angiotensin II, endothelin-1, and norepinephrine.
ADP ribosyl (ADPR) cyclases comprise a family of ectoenzymes recently shown to influence cytosolic Ca(2+) concentration in a variety of cell types. At least two ADPR cyclase family members have been identified in mammals: CD38 and CD157. We recently found reduced renal vascular reactivity to angiotensin II (ANG II), endothelin-1 (ET-1), and norepinephrine (NE) in the presence of the broad ADPR cyclase inhibitor nicotinamide. We hypothesized that CD38 mediates effects attributed to ADPR cyclase. We found expression of ADPR cyclases CD38 and CD157 mRNA in spleen, thymus, skin, and preglomerular arterioles of wild-type (WT) animals. Mice lacking CD38 showed decreased CD157 expression in most tissues tested. No difference in systolic or mean arterial pressure was observed between strains in either conscious or anesthetized states, whereas heart rate was reduced 10-20% in CD38-/- animals (P < 0.05). During anesthesia, CD38-/- mice had reduced basal renal blood flow (RBF) and urine excretion (P < 0.05). RBF responses to intravenous injection of ANG II, ET-1, and NE were attenuated approximately 50% in CD38-/- vs. WT mice (P < 0.01 for all). The systemic pressor response to ANG II was decreased in the absence of CD38 (P < 0.01), whereas that to NE was normal (P > 0.05); ET-1 was administered at a nonpressor dose. Nicotinamide effectively inhibited ANG II-induced renal vasoconstriction in WT mice (P < 0.001), but had no effect on renal responses to ANG II in CD38-/- mice (P > 0.5). Overall, our observations indicate the presence of two ADPR cyclase family members in renal preglomerular resistance arterioles and the importance of CD38 participation in acute vascular responses to all three vasoconstrictors in the renal microcirculation.
Thai
Tiffany L
TL
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Arendshorst
William J
WJ
D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology*; D058851:GPI-Linked Proteins; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009536:Niacinamide / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014803:Vitamin B Complex / Q000494:pharmacology
D015703:Antigens, CD; D019332:Endothelin-1; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D014803:Vitamin B Complex; D009536:Niacinamide; D036541:ADP-ribosyl Cyclase; C087521:ADP-ribosyl cyclase 2; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D009638:Norepinephrine