Smooth Muscle PPARγ Mutation Causes Impaired Renal Blood Flow and Salt‐Sensitive Hypertension

Abstract

Failure to vasodilate in systemic and renal vasculature in response to salt loading is a hallmark of salt sensitivity in hypertensive humans and experimental models. Human subjects carrying dominant negative mutations in PPARγ exhibit hypertension while global PPARγ activation consistently lowers blood pressure (BP). To determine whether tissue‐specific actions of PPARγ regulate vascular function, salt sensitivity and BP, we studied mice specifically expressing a human hypertension‐causing mutation in PPARγ (P467L) selectively in smooth muscle (S‐P467L). S‐P467L transgenic mice and non‐transgenic littermate controls (NT) were fed regular diet (0.4% salt) or high salt (HS) diet containing 4% salt for 4 weeks. Salt induced marked elevations in systolic BP in S‐P467L mice (136±4 mmHg salt n=6 vs 121±3 mmHg regular diet n=7, p<0.01, two‐way ANOVA), but not in NT mice (121±4 mmHg salt n=4 vs 116±4.0 mmHg regular diet n=5). Because salt induced similar increases in cardiac output in S‐P467L and NT animals, the pressor effect of salt intake in S‐P467L mice was not due to a larger fluid volume, but likely higher peripheral vascular resistance. In keeping with this, HS‐fed S‐P467L mice, but not NT controls, exhibited severe impairment in acetylcholine (ACh)‐ and sodium nitroprusside (SNP)‐induced vasorelaxation in carotid artery (Maximal relaxation at 30 μM ACh: S‐P467L 31±4.9% n=4 vs. NT 90±1.8% n=6, p<0.01; Maximal relaxation to 30 μM SNP: S‐P467L 38±2.8% n=4 vs. NT 89±2.6% n=6, p<0.01, two‐way ANOVA Repeated Measurements) and in cerebral basilar artery (Maximal relaxation at 100 μM ACh: S‐P467L ‐3.2±9.3% n=7 vs. NT 57±5.9% n=5, p<0.01). Importantly, salt‐induced vascular dysfunction rapidly developed in S‐P467L mice after receiving HS diet for only 3 days, preceding BP elevations. The impaired vasorelaxation in HS‐fed S‐P467L mice was associated with smaller renal artery diameter (S‐P467L 322±21 μm n=6 vs NT 389±22 μm n=5, p<0.05 two‐way ANOVA) and blunted renal blood flow (S‐P467L 36±3.6 μL/min/g n=6 vs. NT 50±6.4 μL/min/g n=5, p<0.05). These changes were not caused by differences in circulating renin‐angiotensin levels or renal sympathetic nerve activity between the two strains. Preliminary data indicated that during the 3rd week of HS diet, S‐P467L mice produced 36% less nitrate/nitrite in 24 hour urine compared to NT controls, which suggested 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 challenge, 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.Support or Funding InformationDr. Jing Wu is supported by an American Heart Association Postdoctoral Fellowship (17POST33660685). This project is funded by R01 HL125603 and R01 HL131689 to Dr. Curt Sigmund.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.