Abstract 094: Smooth Muscle PPARγ Mutation Causes Impaired Renal Blood Flow and Salt-Sensitive Hypertension

Abstract

Mutations in PPARγ cause hypertension (HT) while PPARγ activation lowers blood pressure (BP) in humans. To determine if vascular smooth muscle (VSM) PPARγ regulates salt sensitivity, we studied transgenic mice selectively expressing a HT-causing PPARγ mutant in VSM (S-P467L) and non-transgenic littermates (NT) fed a 4% high salt (HS) diet for 4 weeks. Salt equally suppressed plasma renin in both strains, but S-P467L mice exhibited increased systolic BP (S-P467L 136±3 mmHg vs NT 124±2 mmHg, p<0.01) and pulse wave velocity (3.1±0.1 vs 2.7±0.1 m/s, p<0.01) in response to HS. The salt-induced HT was not associated with changes in diastolic BP, sympathetic nerve activity, heart rate, or cardiac output. Thus, the pressor effect of HS was likely due to higher peripheral vascular resistance. HS-fed S-P467L mice developed impaired acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation in carotid (Max ACh relaxation: 31±4.9% vs 90±1.8%, p<0.01; Max SNP relaxation: 38±2.8% vs 89±2.6%, p<0.01) and basilar artery (Max ACh relaxation: -3.2±9.3% vs 57±5.9%, p<0.01). The impaired vasodilation rapidly developed after 3-day HS diet, preceding salt-induced BP elevation. Pre-incubation with a cyclooxygenase inhibitor indomethacin normalized ACh/SNP relaxation responses, and preliminary mass spectrometry indicated HS increased prostaglandin E2 in S-P467L aortas. HS-fed S-P467L mice had smaller renal artery luminal diameter (322±21 vs 389±22 μm, p<0.05) and blunted renal blood flow (36±3.6 vs. 50±6.4 μL/min/g, p<0.05). During the 4 th week of HS diet, S-P467L mice produced 31% less nitrate/nitrite in 24 hour urine compared to NT controls (2.2±0.3 vs 3.2±0.4 μmol, p<0.05), suggesting blunted renal bioavailability of nitric oxide, a potent inhibitor of Na-K-2Cl cotransporter (NKCC2). This was associated with a declined capacity of HS-fed S-P467L mice to excrete an acute volume/Na + load, which was rescued by an NKCC2 inhibitor furosemide, but not by the Na-Cl-cotransporter inhibitor hydrochlorothiazide. Our data support the novel concept that smooth muscle PPARγ regulates systemic vascular resistance, renal perfusion and tubular sodium transport, and loss of these protective actions of PPARγ predisposes to salt sensitivity and hypertension.