Submitted on May 5, 2005
Accepted on July 5, 2005
Cytochrome P450 dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus
Albert Sarkis1, Osamu Ito2, Takefumi Mori3, Masahiro Kohzuki2, Sadayoshi Ito4, Joseph Verbalis5, Allen W. Cowley, Jr.1, and Richard J. Roman1*
1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Internal Medicine and Rehabilitation Science, Tohoku University, Sendai, Japan
3 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University, Sendai, Japan
4 Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University, Sendai, Japan
5 Department of Medicine, Georgetown University, Washington DC, USA
* To whom correspondence should be addressed. E-mail: rroman{at}mcw.edu.
This study compared the renal metabolism of arachidonic acid in Brattleboro (BB)
(vasopressin-deficient) and Long-Evans (LE) control rats and the effects of a cytochrome
P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT) on renal function in these animals.
The production of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical and outer
medullary microsomes was significantly greater in BB than in LE rats (155±16 vs. 92±13
and 59±7 vs. 33±3 pmol/min/mg protein). Renal cortical epoxygenase activity was not
different in these strains. The expression of CYP4A proteins was 58% and 78% higher in
the renal cortex and outer medulla of BB than in LE rats. Chronic treatment of BB rats with
a vasopressin type 2 receptor agonist for one week normalized the renal production of
20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little
effects on renal function in LE rats. However, urine flow increased by 54% and urine
osmolarity decreased by 33% in BB rats treated with ABT. Plasma levels of oxytocin fell
significantly from 7.2±1.3 to 3.9±1.0 pg/ml. The effects of ABT in BB rats were attenuated
by chronic infusing of oxytocin (0.7ng/min/100g) to maintain fixed high plasma levels of
this hormone. These results indicate that the expression of CYP4A protein and the renal formation of 20-HETE are elevated in the kidney of BB rats due to a lack of vasopressin,
and that chronic blockade of the formation of 20-HETE and EETs with ABT promotes
water excretion in vasopressin-deficient BB rats by reducing the circulating levels of
oxytocin which is a weak vasopressin agonist.
