Involvement of cytochrome P-450 1B1 in renal dysfunction, injury, and inflammation associated with angiotensin II-induced hypertension in rats

Brett L. Jennings, Larry J. Anderson, Anne M. Estes, Xiao R. Fang, Chi Young Song, William B. Campbell, Kafait Malik

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Abstract

We investigated the contribution of cytochrome P-450 1B1 (CYP1B1) to renal dysfunction and organ damage associated with ANG II-induced hypertension in rats. ANG II (300 ng·kg -1·min -1) or vehicle were infused for 2 wk, with daily injections of a selective CYP1B1 inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS; 300 μg/kg ip), or its vehicle. ANG II increased blood pressure and renal CYP1B1 activity that were prevented by TMS. ANG II also increased water intake and urine output, decreased glomerular filtration rate, increased urinary Na + and K + excretion, and caused proteinuria, all of which were prevented by TMS. ANG II infusion caused hypertrophy, endothelial dysfunction, and increased reactivity of renal and interlobar arteries to vasoconstrictor agents and renal vascular resistance and interstitial fibrosis as indicated by accumulation of α-smooth muscle actin, fibronectin, and collagen, and inflammation as indicated by increased infiltration of CD-3 + cells; these effects were inhibited by TMS. ANG II infusion also increased production of reactive oxygen species (ROS) and activities of NADPH oxidase, ERK1/2, p38 MAPK, and c-Src that were prevented by TMS. TMS alone had no effect on any of the above parameters. These data suggest that CYP1B1 contributes to the renal pathophysiological changes associated with ANG IIinduced hypertension, most likely via increased ROS production and activation of ERK1/2, p38 MAPK, and c-Src and that CYP1B1 could serve as a novel target for treating renal disease associated with hypertension.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume302
Issue number4
DOIs
StatePublished - Feb 1 2012

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Angiotensin II
Cytochrome P-450 Enzyme System
Hypertension
Inflammation
Kidney
Wounds and Injuries
p38 Mitogen-Activated Protein Kinases
Reactive Oxygen Species
NADPH Oxidase
Vasoconstrictor Agents
Renal Artery
Glomerular Filtration Rate
Proteinuria
Fibronectins
Vascular Resistance
Hypertrophy
Drinking
Smooth Muscle
Actins
Fibrosis

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Involvement of cytochrome P-450 1B1 in renal dysfunction, injury, and inflammation associated with angiotensin II-induced hypertension in rats. / Jennings, Brett L.; Anderson, Larry J.; Estes, Anne M.; Fang, Xiao R.; Song, Chi Young; Campbell, William B.; Malik, Kafait.

In: American Journal of Physiology - Renal Physiology, Vol. 302, No. 4, 01.02.2012.

Research output: Contribution to journalArticle

Jennings, Brett L. ; Anderson, Larry J. ; Estes, Anne M. ; Fang, Xiao R. ; Song, Chi Young ; Campbell, William B. ; Malik, Kafait. / Involvement of cytochrome P-450 1B1 in renal dysfunction, injury, and inflammation associated with angiotensin II-induced hypertension in rats. In: American Journal of Physiology - Renal Physiology. 2012 ; Vol. 302, No. 4.
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