Regulation of blood pressure, natriuresis and renal thiazide/amiloride sensitivity in PPARα null mice

Abstract

This study evaluated the role of PPARα in renal function and whether PPARα knockout (KO) mice are hypertensive or salt‐sensitive. We hypothesize that PPARα modulation of ion transport defines the capacity for sodium excretion (UNaV). PPARα KO and wild‐type (WT) mice were placed on a normal salt (NS, 0.5% NaCl) or high salt (8% NaCl, HS) diet for 28 days and mean arterial blood pressure (MABP) and heart rate (HR) determined. In a group of anesthetized animals on NS diet, pressure natriuresis (P/N) was determined and in another group, acute sodium load (0.9% NaCl) was administered and UNaV compared in mice pretreated with amiloride (200 µg/kg) or hydrochlorothiazide (3 mg/kg), in vivo measurements of sodium hydrogen exchanger or Na‐Cl‐cotransporter activity, respectively. MABP and HR were similar in PPARα KO and WT mice placed on a NS diet (116±6 mmHg, 587±40 beats/min, KO; 116±4 mmHg, 551±20 beats/min, WT). HS diet increased MABP to a greater extent in KO mice (Δ = 29±3 vs 14±3 mmHg, p<0.05) as did proteinuria (8‐ vs 2.5‐fold, p<0.05). P/N was blunted in untreated KO mice. In response to an acute NaCl‐load, UNaV was faster in PPARα KO mice (4.31±1.11 vs 0.77±0.31 µmol, p<0.05). However, UNaV was unchanged in hydrochlorothiazide‐treated KO mice but increased 6.9‐fold in WT mice. Similarly, UNaV was less in amiloride‐treated KO mice (3.4‐ vs 15.5‐fold). These data suggest that PPARα participates in pressure natriuresis and affects Na transport via amiloride‐ and thiazide‐sensitive mechanisms. Thus, despite defective fatty acid oxidation, PPARα null mice are not hypertensive but develop salt‐sensitive hypertension.