Faculty Collaboration Database

Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin II in mice. Hypertension 2012 Feb;59(2):348-54

Date

12/21/2011

Pubmed ID

22184325

Pubmed Central ID

PMC3268066

DOI

10.1161/HYPERTENSIONAHA.111.183301

Scopus ID

2-s2.0-84856237440 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Cytochrome P450 1B1 contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of cytochrome P450 1B1 to renal dysfunction and injury associated with angiotensin II-induced hypertension in male Cyp1b1(+/+) and Cyp1b1(-/-) mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1b1(+/+) mice; this increase was significantly reduced in Cyp1b1(-/-) mice. Angiotensin II increased renal Cyp1b1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1b1(+/+) but not Cyp1b1(-/-) mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na(+) and K(+) excretion, and caused proteinuria and albuminuria in Cyp1b1(+/+) mice that was diminished in Cyp1b1(-/-) mice. Infusion of angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1b1(+/+) mice, which was minimized in Cyp1b1(-/-) mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1b1(+/+) but not Cyp1b1(-/-) mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with angiotensin II-induced hypertension in mice depend on cytochrome P450 1B1 activity, thus indicating that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension.

Author List

Jennings BL, Anderson LJ, Estes AM, Yaghini FA, Fang XR, Porter J, Gonzalez FJ, Campbell WB, Malik KU

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
Aryl Hydrocarbon Hydroxylases
Blood Pressure
Cytochrome P-450 CYP1B1
Disease Models, Animal
Endothelium, Vascular
Extracellular Signal-Regulated MAP Kinases
Fibrosis
Hypertension
Kidney
Male
Mice
Mice, Knockout
NADPH Oxidases
Protein-Tyrosine Kinases
Reactive Oxygen Species
Sodium
Vascular Resistance
src-Family Kinases