title: Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.
abstract: Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension.
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: Paramita
authors.initials: P
authors.lastname: Pati
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: David J R
authors.initials: DJ
authors.lastname: Fulton
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: Yusi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: Julia
authors.initials: J
authors.lastname: Kitchens
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.).
authors.forename: David W
authors.initials: DW
authors.lastname: Stepp
authors.affiliation: From the Departments of Pharmacology and Toxicology (P.P., D.J.R.F., J.K., R.D.R.), Medicine (Z.B.), and Physiology (D.W.S.), Vascular Biology Center (D.J.R.F., Z.B., F.C., Y.W., D.W.S.), Medical College of Georgia at Augusta University; and Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington (L.A.C.). rrudic@gru.edu.
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Rudic
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D004039:Diet, Sodium-Restricted; D004195:Disease Models, Animal; D006973:Hypertension / Q000178:diet therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
chemical_list: D017673:Sodium Chloride, Dietary; D000804:Angiotensin II
keywords: aging; angiotensin; circadian; hypertension; hypertrophy; renin; sodium