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

1.为阐明慢性运动对肾脏保护作用的机制，测定了慢性运动对花生四烯酸（AA）细胞色素P-450 （CYP）代谢的影响。Wistar-Kyoto大鼠分为对照组和运动组。8周后，测定肾脏和肝脏微粒体代谢产物AA的产量。在肾脏中，运动增加了20-羟基二十碳四烯酸（20-HETE）的产生，而不影响环氧二十碳三烯酸（EETs）的产生。在肝脏中，运动不会影响20-HETE的产生，但会降低eet的产生。肾脏中20-HETE生成的增加可能有助于慢性运动对肾脏的保护作用。CYP4家族催化AA的ω-羟基化。在大鼠中，CYP4A在近端小管中表达，在肾小球前微血管、肾小球和厚升肢（TAL）中表达量较低，但在集合管中未见表达。在人类中，CYP4A和CYP4F在近端小管中表达，在TAL和集合管中表达较低，但在肾小球和肾血管中不表达。比较了抗利尿激素缺乏的Brattleboro （BB）大鼠和对照组Long-Evans （LE）大鼠肾脏中AA的CYP代谢及CYP抑制剂1-氨基苯并三唑（ABT）对肾功能的影响。BB大鼠肾微粒体产生的20-HETE明显高于LE大鼠。CYP4A蛋白在BB大鼠中的表达高于LE大鼠。用ABT慢性阻断20-HETE和eet的形成对LE大鼠肾功能影响不大。然而，ABT处理后，BB大鼠GFR和尿流量增加，尿渗透压降低，这些结果表明，肾脏20-HETE形成的升高可能调节BB大鼠GFR和水排泄。

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.