Regulation of cytochrome P-450 4A activity by peroxisome proliferator-activated receptors in the rat kidney

The localization of cytochrome P-450 4A, peroxisome proliferator-activated receptor (PPAR) α, and PPARγ proteins, and the inducibility of P-450 4A expression and activity by PPAR agonists were determined in the rat kidney. The expressions of these proteins in isolated nephron segments were evaluated by immunoblot analysis, and the production of 20-hydroxyeicosatetraenoic acid (20-HETE was measured as P-450 4A activity. P-450 4A proteins were expressed predominantly in the proximal tubule (PT), with lower expression in the preglomerular arteriole (Art), glomerulus (Glm), and medullary thick ascending limb (mTAL), but their expression was not detected in the inner medullary collecting duct (IMCD). PPARα protein was expressed in the PT and mTAL, and PPARγ protein was expressed in the IMCD and mTAL. Treatment with clofibrate, the PPARα agonist, increased P-450 4A protein levels and the production of 20-HETE in microsomes prepared from the renal cortex, whereas treatment with pioglitazone, the PPARγ agonist, affected neither of them. These results indicate that PPARα and PPARγ proteins are localized in different nephron segments and the inducibility of P-450 4A expression and activity by the PPAR agonists correlates with the nephron-specific localization of the respective PPAR isoforms.