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.