Abstract
Smooth Muscle PPARgamma Mutation Causes Impaired Renal Blood Flow and Salt‐Sensitive Hypertension
The FASEB journal, Vol.33(S1), pp.569.18-569.18
04/2019
DOI: 10.1096/fasebj.2019.33.1_supplement.569.18
Abstract
Failure to vasodilate the systemic and renal vasculature in response to salt loading is a hallmark of salt sensitive hypertension (HT). Human subjects carrying dominant negative mutations in PPARgamma (PPARG) exhibit early onset HT while global PPARG activation consistently lowers blood pressure (BP). To determine whether tissue‐specific actions of PPARG regulate systemic and renal vascular function, salt sensitivity and BP, we studied mice specifically expressing a human HT‐causing mutation in PPARG P467L in smooth muscle (S‐P467L). S‐P467L transgenic mice and non‐transgenic 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 (135 ± 2 mmHg HS vs 121 ± 4 mmHg regular diet), but not in NT mice (121 ± 5 mmHg HS vs 118 ± 3 mmHg regular diet). S‐P467L and NT animals exhibited identical cardiac output at baseline and under chronic HS; thus 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‐consuming S‐P467L mice, but not NT controls, exhibited severe impairment in acetylcholine‐ and sodium nitroprusside‐induced vasorelaxation in carotid artery (Maximal relaxation at 30 μM acetylcholine: S‐P467L 35 ± 4% vs. NT 90 ± 2%), basilar artery (S‐P467L −3 ± 9% vs. NT 70 ± 5%), and first order renal arteries branches (S‐P467L 34 ± 4% vs. NT 76 ± 4%). Importantly, salt‐induced vascular dysfunction rapidly developed in S‐P467L mice after receiving HS diet for only 3 days, preceding the BP elevation. In line with the impaired renovascular relaxation, S‐P467L mice failed to adapt their renal blood flow (RBF) to HS (HS‐induced increases in RBF: S‐P467L 3 μL/min/g vs. NT 20 μL/min/g). The impaired renovascular dilation and blunted RBF was not caused by differences in circulating renin‐angiotensin levels or renal sympathetic nerve activity between the two strains. In the 3rd week of HS diet, S‐P467L mice produced 31% less nitrate/nitrite in 24 hour urine compared to NT controls, which was indicative of blunted renal bioavailability of nitric oxide, a potent inhibitor of Na‐K‐2Cl cotransporter (NKCC2). These changes were associated with a declined capacity of HS‐fed S‐P467L mice to excrete excess sodium and volume challenge, which was rescued by an NKCC2 inhibitor furosemide, but not by the Na‐Cl‐cotransporter inhibitor thiazide. Further supporting a role of NKCC2, a single dose of furosemide (20 mg/kg) induced a larger decrease in systolic BP in salt‐consuming S‐P467L mice (S‐P467L HS −16 ± 3 mmHg, S‐P467L regular diet −5 ± 2 mmHg, NT HS −6 ± 2 mmHg, and NT regular diet −6 ± 2 mmHg), while thiazide did not. Our data support the novel concept that smooth muscle PPARG regulates systemic and renal vascular resistance, renal perfusion and tubular sodium transport, and loss of these protective actions of PPARG predisposes to salt sensitivity and hypertension.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- Smooth Muscle PPARgamma Mutation Causes Impaired Renal Blood Flow and Salt‐Sensitive Hypertension
- Creators
- Jing Wu - The University of IowaLarry Agbor - The University of IowaAnand Nair - The University of IowaMasashi Mukohda - The University of IowaShi Fang - The University of IowaPablo Nakagawa - The University of IowaDonald A Morgan - The University of IowaKamal Rahmouni - The University of IowaRobert M Weiss - The University of IowaKatherine Gotlinger - New York Medical CollegeMichal Schwartzman - New York Medical CollegeCurt D Sigmund - The University of Iowa
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.33(S1), pp.569.18-569.18
- Publisher
- The Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fasebj.2019.33.1_supplement.569.18
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 1
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984071960502771
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