PS 07-05 ANGIOTENSIN II UPREGULATES CYTOCHROME-450 4A EXPRESSION IN RAT KIDNEY THROUGH TYPE 1 RECEPTOR

Objective: 20-hydroxyeicosatetraenoic acids (20-HETE) which is the major metabolites of arachidonic acid catalysed by cytochrome P-450 (CYP) 4A isoforms, is an important substance for the regulation of vascular tone and renal tubular function. Previous studies showed that angiotensin II (Ang II) stimulated the renal CYP activity and 20-HETE production in preglomerular arteries and renal tubules. However, the regulation of CYP4A expressions by Ang II in kidney has not been fully clarified. Design and Method: Experiments were performed on 8 week-old SD rats at Ang II at low dose (AL, 0.17 mg/kg/min, sc) and high dose (AH, 0.70 mg/kg/day, sc) by using osmotic mini pump, with or without angiotensin II type 1 (AT1) receptor blocker candesartan (CAN1, 1 mg/kg/day; CAN3, 3 mg/kg/day in drinking water) which were fed for 1 week. Systolic blood pressure (SBP) was measured by tail-cuff method. The expressions of CYP4A isoform in the kidney section were examined by immunoblot analysis. Results: Ang II significantly increased SBP in AH group, but not in AL group (control, 109 ± 2; AL, 115 ± 5; AH, 164 ± 8 mmHg). In the control group the CYP4A1, 4A2, and 4A8 proteins were highly expressed in the renal cortex, lowly expressed in the inner strip of outer medulla, and barely detectable in the inner medulla. Ang II dose-dependently increased the all CYP4A isoform expressions in the renal cortex and the inner strip of outer medulla (CYP4A1, 24% and 222%; CYP4A2, by 51% and 258%; CYP4A8, by 52% and 550% at high dose group). Candesartan treatment alone did not affect the CYP4A isoform expression, but it did dose-dependently inhibit the Ang II-increased CYP4A expression. Conclusions: Ang II increases CYP4A isoform expressions in the kidney through AT1 receptor. The Ang II-unregulated CYP4A expressions may play an important role in hypertension and renal function.