Abstract 099: Smooth Muscle PPARγ Mutation Causes Salt-sensitive Hypertension

Abstract

Abnormal increase in renal salt retention is traditionally believed to be an early pathophysiological event in the causation of salt-sensitive hypertension, whereas increase in systemic vascular resistance (SVR) is a secondary response caused by autoregulation. However, recent studies show that salt-resistant subjects vasodilate and reduce SVR during salt loading, while salt-sensitive humans fail to vasodilate and exhibit salt-induced blood pressure (BP) elevation. Therefore, we tested the hypothesis that primary vascular dysfunction predisposes to salt sensitive hypertension. We used mice with smooth muscle-specific expression of a human hypertension-causing mutation in PPARγ P467L (S-P467L). S-P467L transgenic mice and non-transgenic controls (NT) were fed regular diet (0.4% salt) or high salt diet (4% salt) for 4 weeks. S-P467L mice, but not NT controls, exhibited severe impairment in acetylcholine- and sodium nitroprusside-induced vasorelaxation (31±4.9% S-P467L salt vs. 70±9.5% regular diet, maximal relaxation at 30 μM acetylcholine). This was associated with salt-induced systolic BP elevation in S-P467L mice (142±5 mmHg salt vs 127±2 mmHg regular diet), but not in NT mice (120±2.7 mmHg salt vs 115±4.0 mmHg). These changes were not due to differences in food intake, weight gain or renal sympathetic nerve activity between the two strains. In the 3 rd week of high salt diet, S-P467L mice and NT controls both had increased water intake by 3-fold compared to those on regular diet; however, S-P467L mice excreted 32% less urine and produced 36% less NO in the kidney as indicated by 24-hour urinary nitrate/nitrite. To assess renal function, mice were subjected to an acute saline challenge (10% body weight, i.p. injection). S-P467L mice exhibited a marked decline in their capacity to excrete this volume/sodium load, indicative of renal dysfunction. Of note, the impaired vasorelaxation in S-P467L occurred as early as day 3 of high salt diet, while renal dysfunction did not develop until day 10, suggesting that vascular dysfunction may serve as an initiation mechanism that reinforces salt-induced hemodynamic changes. These data supports the concept that vascular dysfunction may predispose to renal abnormalities including increased salt sensitivity.