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Am J Physiol Renal Physiol 289: F1333-F1340, 2005. First published July 12, 2005; doi:10.1152/ajprenal.00188.2005
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Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

Albert Sarkis,1 Osamu Ito,2 Takefumi Mori,1,3 Masahiro Kohzuki,2 Sadayoshi Ito,3 Joseph Verbalis,4 Allen W. Cowley, Jr.,1 and Richard J. Roman1

1Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; 2Department of Internal Medicine and Rehabilitation Science, 3Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; and 4Department of Medicine, Georgetown University, Washington, District of Columbia

Submitted 5 May 2005 ; accepted in final form 5 July 2005

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 P-450 (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–1·mg protein–1). 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 1 wk normalized the renal production of 20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effect 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 infusion of oxytocin (0.7 ng·min–1·100 g–1) 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.

Brattleboro rats; 20-hydroxyeicosatetraenoic acid; cytochrome P-450; epoxyeicosatrienoic acid; renal hemodynamics


Address for reprint requests and other correspondence: R. J. Roman, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 (e-mail: rroman{at}mcw.edu)






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