title: Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice.
abstract: Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ng·kg(-1)·min(-1)) infused by miniosmotic pumps for 2 wk in female Cyp1b1(+/+) mice did not alter water consumption, urine output, Na(+) excretion, osmolality, or protein excretion. However, in Cyp1b1(-/-) mice, ANG II infusion significantly increased (P < 0.05) water intake (5.50 ± 0.42 ml/24 h with vehicle vs. 8.80 ± 0.60 ml/24 h with ANG II), urine output (1.44 ± 0.37 ml/24 h with vehicle vs. 4.30 ± 0.37 ml/24 h with ANG II), and urinary Na(+) excretion (0.031 ± 0.016 mmol/24 h with vehicle vs. 0.099 ± 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 ± 79 mosM/kg with vehicle vs. 1,280 ± 205 mosM/kg with ANG II), and caused proteinuria (2.60 ± 0.30 mg/24 h with vehicle vs. 6.96 ± 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial α-smooth muscle actin, collagen, and transforming growth factor-β in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid-reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17β-estradiol metabolite 2-methoxyestradiol in Cyp1b1(-/-) but not Cyp1b1(+/+) mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17β-estradiol.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Brett L
authors.initials: BL
authors.lastname: Jennings
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Moore
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Ajeeth K
authors.initials: AK
authors.lastname: Pingili
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Anne M
authors.initials: AM
authors.lastname: Estes
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Fang
authors.affiliation: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and.
authors.forename: Alie
authors.initials: A
authors.lastname: Kanu
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; kmalik@uthsc.edu.
authors.forename: Kafait U
authors.initials: KU
authors.lastname: Malik
mesh_terms: D000804:Angiotensin II; D000818:Animals; D002374:Catalase / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004326:Drinking; D004958:Estradiol / Q000031:analogs & derivatives / Q000652:urine; D005260:Female; D005355:Fibrosis; D005838:Genotype; D006973:Hypertension / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009318:Natriuresis; D018384:Oxidative Stress; D010641:Phenotype; D012084:Renin-Angiotensin System; D012737:Sex Factors; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014554:Urination
chemical_list: D013481:Superoxides; D000804:Angiotensin II; C037233:2-methylestradiol; C002744:3-nitrotyrosine; D014443:Tyrosine; D004958:Estradiol; D002374:Catalase; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D013482:Superoxide Dismutase; D019255:NADPH Oxidases
keywords: angiotensin II; cytochrome P-450 1B1-deficient female mice; increased oxidative stress; kidney dysfunction; reduced antioxidant activity