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. 2012 Feb;59(2):415-20.
doi: 10.1161/HYPERTENSIONAHA.111.184291. Epub 2011 Dec 19.

p47(phox) is required for afferent arteriolar contractile responses to angiotensin II and perfusion pressure in mice

En Yin Lai  1 , Glenn Solis, Zaiming Luo, Mattias Carlstrom, Kathryn Sandberg, Steven Holland, Anton Wellstein, William J Welch, Christopher S Wilcox
Affiliations

p47(phox) is required for afferent arteriolar contractile responses to angiotensin II and perfusion pressure in mice

En Yin Lai et al. Hypertension. 2012 Feb.

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.

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Figures

Figure 1
Figure 1
Mean ± SEM values for telemetric mean arterial pressure of p47phox +/+ (solid squares and continuous lines; n = 6) and p47phox -/-(open circles and broken lines n = 7) mice before and during angiotensin II (400 ng · kg-1 · min-1 · sc) during the daytime (asleep) in panel A and the nighttime (awake) in panel B. Comparing groups: *, P<0.05.
Figure 2
Figure 2
Mean ± SEM values (n = 6-9 per group) for mice studied under anesthesia showing renal cortical NADPH oxidase activity (panel A), arterial pressure (panel B), glomerular filtration rate (panel C), renal blood flow (panel D), and renal vascular resistance (panel E) in groups of p47phox +/+ and -/- mice given a vehicle (open boxes) or Ang II (400 · kg-1 · min-1 sc) for 12 days. Compared to equivalent p47phox +/+ mice: a, P<0.05.
Figure 3
Figure 3
Mean ± SEM values (n = 4 - 7) for afferent arteriolar diameter (Panel A) and changes in diameter from baseline (Panel B) during bath addition of angiotensin II to p47phox +/+ mice infused with vehicle (solid circles and continuous lines) or angiotensin II (open circles and broken lines) or p47phox -/- mice infused with vehicle (solid triangles and continuous lines) or angiotensin II (open triangles and broken lines). Significance of difference between groups: * P<0.05. Significance of difference from vehicle: a, P<0.05.
Figure 4
Figure 4
Mean ± SEM values (n= 4 - 7) for afferent arteriolar diameter (panel A), change in diameter (panel B) and active wall tension (panel C) during increases in renal perfusion pressure. Data are shown for vessels from p47phox +/+ mice infused with vehicle (solid circles and continuous lines) or angiotensin II (open circles and broken lines) or p47phox -/- mice infused with vehicle (solid triangles and continuous lines) or angiotensin II (open triangles and broken lines). Significance of difference between groups: * P<0.05.
Figure 5
Figure 5
Mean ± SEM values (n= 5 to 7) for increases in ethidium: dihydroethidium ratio of afferent arterioles from p47phox +/+ mice (solid black) and p47phox -/- mice (open box). Data are shown for changes with 10-6 M angiotensin II or increased perfusion from 40-80 mmHg.
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