This study evaluated the role of PPAR in renal function and whether PPAR knockout (KO) mice are hypertensive or salt-sensitive. We hypothesize that PPAR modulation of ion transport defines the capacity for sodium excretion (U_NaV). PPAR 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 U_NaV 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 PPAR 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, U_NaV was faster in PPAR KO mice (4.31±1.11 vs 0.77±0.31 µmol, p<0.05). However, U_NaV was unchanged in hydrochlorothiazide-treated KO mice but increased 6.9-fold in WT mice. Similarly, U_NaV was less in amiloride-treated KO mice (3.4- vs 15.5-fold). These data suggest that PPAR participates in pressure natriuresis and affects Na transport via amiloride- and thiazide-sensitive mechanisms. Thus, despite defective fatty acid oxidation, PPAR null mice are not hypertensive but develop salt-sensitive hypertension.