Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

Albert Sarkis, Osamu Ito, Takefumi Mori, Masahiro Kohzuki, Sadayoshi Ito, Joseph Verbalis, Allen W. Cowley, Richard J. Roman

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)F1333-F1340
JournalAmerican Journal of Physiology - Renal Physiology
Volume289
Issue number6 58-6
DOIs
Publication statusPublished - 2005 Dec

Keywords

  • 20-hydroxyeicosatetraenoic acid
  • Brattleboro rats
  • Cytochrome P-450
  • Epoxyeicosatrienoic acid
  • Renal hemodynamics

ASJC Scopus subject areas

  • Physiology
  • Urology

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