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: Brett L Jennings, Joseph A Moore, Ajeeth K Pingili, Anne M Estes, Xiao R Fang, Alie Kanu, Frank J Gonzalez, Kafait U Malik
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 308 Issue 9 Pg. F981-92 (May 01 2015) ISSN: 1522-1466 [Electronic] United States
• PMID: 25694484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Superoxides
• Angiotensin II
• 2-methylestradiol
• 3-nitrotyrosine
• Tyrosine
• Estradiol
• Catalase
• Cyp1b1 protein, mouse
• Cytochrome P-450 CYP1B1
• Superoxide Dismutase
• NADPH Oxidases

Topics

• Angiotensin II
• Animals
• Catalase (metabolism)
• Cytochrome P-450 CYP1B1 (deficiency, genetics, metabolism)
• Disease Models, Animal
• Drinking
• Estradiol (analogs & derivatives, urine)
• Female
• Fibrosis
• Genotype
• Hypertension (complications, enzymology, genetics, physiopathology)
• Kidney (enzymology, pathology, physiopathology)
• Kidney Diseases (enzymology, etiology, genetics, pathology, physiopathology, prevention & control)
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidases (metabolism)
• Natriuresis
• Oxidative Stress
• Phenotype
• Renin-Angiotensin System
• Sex Factors
• Superoxide Dismutase (metabolism)
• Superoxides (metabolism)
• Tyrosine (analogs & derivatives, metabolism)
• Urination