Inability to Upregulate Cytochrome P450 4A and 2C Causes Salt Sensitivity in Young Sprague-Dawley Rats

Abstract

Young Sprague-Dawley rats develop high blood pressure (BP) when exposed to a high salt intake, whereas adult ones generally do not. We investigated the role of renal cytochromes P450 4A (CYP 4A) and 2C (CYP 2C) in maintaining normal BP. Young (age 5 weeks) and adult (age 53 weeks) Sprague-Dawley rats were given either 20 mmol sodium carbonate (vehicle for clofibrate) or 0.9% saline to drink for 3 weeks. Some young animals received the peroxisome proliferator activated receptor (PPAR)alpha agonist clofibrate (80 mg daily). We measured tail-cuff and intra-arterial BP, weight change, sodium balance, 20-hydroxyeicosatetraenoic acid (20-HETE) excretion (by high-performance liquid chromatography), and renal expression of CYP 4A and CYP 2C (by real-time reverse transcriptase-polymerase chain reaction). Saline-treated adult animals remained normotensive: systolic BP (SBP) 117 +/- 2 mm Hg v 117 +/- 1 mm Hg in control animals. In contrast, young rats given saline developed increased SBP: 134 +/- 2 mm Hg v 115 +/- 2 mm Hg in control animals (P < . 001). Interestingly, clofibrate lowered SBP to 102 +/- 2 mm Hg in saline-treated young rats but had no effect in control animals (114 +/- 2 mm Hg). Adult rats given saline increased renal expression of CYP 4A and 2C and excreted more 20-HETE. However, young rats given saline showed no induction, and even reduced CYP 4A and 2C, decreased urinary 20-HETE excretion, and retained sodium. Clofibrate increased renal CYP and 20-HETE excretion and prevented sodium retention. The products of renal CYP4A and 2C, including 20-HETE, aid in excreting salt. Animals that are unable to increase renal 20-HETE formation do not excrete sodium and are prone to hypertension.