Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice

Brett L. Jennings, Joseph A. Moore, Ajeeth Pingili, Anne M. Estes, Xiao R. Fang, Alie Kanu, Frank J. Gonzalez, Kafait Malik

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Abstract

Recently, we demonstrated in femalemice that protection against ANG II-induced hypertension andassociated cardiovascular changes depend on cytochrome P-450(CYP)1B1. The present study was conducted to determine if Cyp1b1gene disruption ameliorates renal dysfunction and organ damageassociated with ANG II-induced hypertension in female mice. ANG II(700 ng·kg-1·min-1) infused by miniosmotic pumps for 2 wk infemale Cyp1b1+/+ mice did not alter water consumption, urineoutput, Na+ excretion, osmolality, or protein excretion. However, inCyp1b1-/- 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/24h 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/24h with ANG II), decreased osmolality (2,630 ± 79 mosM/kg withvehicle 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 withANG II). Infusion of ANG II caused renal fibrosis, as indicated by anaccumulation 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 urinaryexcretion of thiobarburic acid-reactive substances and reduced theactivity of antioxidants and urinary excretion of nitrite/nitrate and the 17β-estradiol metabolite 2-methoxyestradiol in Cyp1b1-/- but notCyp1b1+/+ mice. These data suggest that Cyp1b1 plays a critical rolein female mice in protecting against renal dysfunction and end-organdamage associated with ANG II-induced hypertension, in preventingoxidative stress, and in increasing activity of antioxidant systems,most likely via generation of 2-methoxyestradiol from 17β-estradiol.

Original languageEnglish (US)
Pages (from-to)F981-F992
JournalAmerican Journal of Physiology - Renal Physiology
Volume308
Issue number9
DOIs
StatePublished - May 1 2015

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Angiotensin II
Cytochrome P-450 Enzyme System
Hypertension
Kidney
Genes
Osmolar Concentration
Drinking
Antioxidants
Transforming Growth Factors
Nitrites
Proteinuria
Smooth Muscle
Actins
Estradiol
Fibrosis
Collagen
Urine
Acids
Proteins
2-methoxyestradiol

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice. / Jennings, Brett L.; Moore, Joseph A.; Pingili, Ajeeth; Estes, Anne M.; Fang, Xiao R.; Kanu, Alie; Gonzalez, Frank J.; Malik, Kafait.

In: American Journal of Physiology - Renal Physiology, Vol. 308, No. 9, 01.05.2015, p. F981-F992.

Research output: Contribution to journalArticle

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AU - Gonzalez, Frank J.

AU - Malik, Kafait

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