title: p47(phox) is required for afferent arteriolar contractile responses to angiotensin II and perfusion pressure in mice.
abstract: Myogenic and angiotensin contractions of afferent arterioles generate reactive oxygen species. Resistance vessels express neutrophil oxidase-2 and -4. Angiotensin II activates p47(phox)/neutrophil oxidase-2, whereas it downregulates NOX-4. Therefore, we tested the hypothesis that p47(phox) enhances afferent arteriolar angiotensin contractions. Angiotensin II infusion in p47(phox) +/+ but not -/- mice increased renal cortical NADPH oxidase activity (7±1-12±1 [P<0.01] versus 5±1-7±1 10(3) · RLU · min(-1) · μg protein(-1) [P value not significant]), mean arterial pressure (77±2-91±2 [P<0.005] versus 74±2-77±1 mm Hg [P value not significant]), and renal vascular resistance (7.5±0.4-10.1±0.7 [P<0.01] versus 7.9±0.4-8.3±0.4 mm Hg/mL · min(-1) · gram kidney weight(-1) [P value not significant]). Afferent arterioles from p47(phox) -/- mice had a lesser myogenic response (3.1±0.4 versus 1.4±0.2 dynes · cm(-1) · mm Hg(-1); P<0.02) and a lesser (P<0.05) contraction to 10(-6) M angiotensin II (diameter change +/+: 9.3±0.2-3.4±0.6 μm versus -/-: 9.9±0.6-7.5±0.4 μm). Angiotensin and increased perfusion pressure generated significantly (P<0.05) more reactive oxygen species in p47(phox) +/+ than -/- arterioles. Angiotensin II infusion increased the maximum responsiveness of afferent arterioles from p47(phox) +/+ mice to 10(-6) M angiotensin II yet decreased the response in p47(phox) -/- mice. The angiotensin infusion increased the sensitivity to angiotensin II only in p47(phox) +/+ mice. We conclude that p47(phox) is required to enhance renal NADPH oxidase activity and basal afferent arteriolar myogenic and angiotensin II contractions and to switch afferent arteriolar tachyphylaxis to sensitization to angiotensin during a prolonged angiotensin infusion. These effects likely contribute to hypertension and renal vasoconstriction during infusion of angiotensin II.
authors.affiliation: Hypertension, Kidney, and Vascular Research Center, Georgetown University Medical Center, NW, Washington, DC 20007, USA.
authors.forename: En Yin
authors.initials: EY
authors.lastname: Lai
authors.forename: Glenn
authors.initials: G
authors.lastname: Solis
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Luo
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlstrom
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sandberg
authors.forename: Steven
authors.initials: S
authors.lastname: Holland
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: William J
authors.initials: WJ
authors.lastname: Welch
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1