Inability to upregulate cytochrome P450 4A and 2C causes salt sensitivity in young Sprague-Dawley rats.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Sankaralingam
Sowndramalingam
S
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Desai
Kaushik M
KM
Glaeser
Hartmut
H
Kim
Richard B
RB
Wilson
Thomas W
TW
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002994:Clofibrate / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000652:urine; D008297:Male; D011507:Proteinuria; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000652:urine; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
D000924:Anticholesteremic Agents; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; C400322:cytochrome P-450 CYP2C subfamily; D012965:Sodium Chloride; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate