Mechanism of renoprotective effect of exercise training : Role of renal cytochrome P-450 metabolism of arachidonic acid

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1.To clarify the mechanism of the renal-protective effects of chronic exercise, the effect of chronic exercise on the cytochrome P-450 (CYP) metabolism of arachidonic acid (AA) was determined. Wistar-Kyoto rats were separated to a control or an exercise group. After 8 weeks, the production of the metabolites of AA by kidney and liver microsomes was measured. In the kidney, exercise increased the production of 20-hydroxyeicosatetraenoic acid (20-HETE), whereas it did not affect the production of epoxyeicosatrienoic acids (EETs). In the liver, exercise did not affect the production of 20-HETE, whereas it decreased the production of EETs. The increased production of 20-HETE in the kidney may contribute to the renal-protective effects of chronic exercise.2.CYP4 family catalyze the ω-hydroxylation of AA. In rat, CYP4A was expressed in the proximal tubule, with lower expression in the preglomerular microvessel, glomerulus and thick ascending limb (TAL), but the expression was not detected in the collecting duct. In human, CYP4A and CYP4F were expressed in the proximal tubules, with lower expression in the TAL and collecting duct, but no expression in the glomerulus or renal vasculatures.3.The renal CYP metabolism of AA in vasopressin-deficient Brattleboro (BB) and control Long-Evans (LE) rats and the effects of a CYP inhibitor, 1-aminobenzotriazole (ABT) on renal function in these animals were compared. The production of 20-HETE by renal microsomes was significantly greater in BB rats than in LE rats. The expression of CYP4A proteins was higher in BB rats than LE rats. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effects on renal function in LE rats. However, GFR and urine flow increased and urine osmolarity decreased in BB rats treated with ABT. These results suggest that the elevating formation of 20-HETE in the kidney may regulate GFR and water excretion in BB rats.