Regulation of blood pressure, natriuresis and renal thiazide/amiloride sensitivity in PPARalpha null mice.
This study evaluated the role of PPARalpha in renal function and whether PPARalpha knockout (KO) mice are hypertensive or salt-sensitive. We hypothesize that PPARalpha modulation of ion transport defines the capacity for sodium excretion (U(Na)V). PPARalpha 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(Na)V compared in mice pretreated with amiloride (200 microg/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 PPARalpha 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 (Delta = 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(Na)V was faster in PPARalpha KO mice (4.31+/-1.11 vs 0.77+/-0.31 micromol, p<0.05). However, U(Na)V was unchanged in hydrochlorothiazide-treated KO mice but increased 6.9-fold in WT mice. Similarly, U(Na)V was less in amiloride-treated KO mice (3.4- vs 15.5-fold). These data suggest that PPARalpha participates in pressure natriuresis and affects Na transport via amiloride- and thiazide-sensitive mechanisms. Thus, despite defective fatty acid oxidation, PPARalpha null mice are not hypertensive but develop salt-sensitive hypertension.
Obih
Patience
P
College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana, USA.
Oyekan
Adebayo O
AO
D000584:Amiloride / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D004232:Diuretics / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D006977:Hypertension, Renal / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D007677:Kidney Function Tests / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009318:Natriuresis / Q000187:drug effects* / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics; D012965:Sodium Chloride / Q000008:administration & dosage / Q000652:urine; D017673:Sodium Chloride, Dietary; D049971:Thiazides / Q000627:therapeutic use*
D004232:Diuretics; D047493:PPAR alpha; D017673:Sodium Chloride, Dietary; D049971:Thiazides; D012965:Sodium Chloride; D000584:Amiloride