Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6/J Mice

Abstract

Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na + ) to high salt (3% Na + ) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal NHE3 (sodium-hydrogen-exchanger 3) and EnaC (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure–depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.

Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

“…A diet high in salt induced a modest increase in blood pressure in both wildtype and renin-b knockout mice. It was recently demonstrated that the C57BL6/J strain is salt-sensitive in response to overactivation of the sympathetic nervous system [30], but this remains controversial as there are other reports indicating that C57BL6/J are salt resistant [31,32]. Contrary to our prediction, renin-b lacking mice did not exhibit an augmented pressor response to salt.…”

Sex-specific adaptations to high-salt diet preserve electrolyte homeostasis with distinct sodium transporter profiles

“…In that same study, we reported, by membrane fractionation, redistribution of transporters to higher density membranes enriched in endosomal markers during HS diet (11). Two recent studies in male mice are informative: Udwan et al (17) implementing surface biotinylation of transporters, measured a 50% fall in surface expression of NHE3 and other transporters along the nephron in male mice fed HS (1.25% Na þ ) and depressed protein pool sizes; Ralph et al (8) measured downregulation of NHE3 mRNA in mice fed 3% Na þ diet (near double the Na þ content in this study). Taken together, the proximal natriuresis during HS diet likely results from smaller pools of active transporters Figure.…”

“…High sodium intake increases thirst and circulatory volume, which provide signals to increase renal excretion of sodium and water to restore circulatory volume balance, independent of changes in blood pressure (1,2). People in modernized cultures around the world chronically consume about twice the daily NaCl intake recommended by the American Heart Association, which can lead to salt-sensitive hypertension driven by elevated inflammation, sympathetic nervous system activation, and intrarenal production of angiotensin II, among other contributors (3)(4)(5)(6)(7)(8)(9). These effectors directly or indirectly activate tubular Na þ transport and, in salt-sensitive individuals, can increase blood pressure, which, via pressure natriuresis, offsets the tubular dysfunction by reducing Na þ reabsorption, matching NaCl excretion to intake (1,10).…”

Single-cell analysis of salt-induced hypertensive mouse aortae reveals cellular heterogeneity and state changes

“…A high dietary intake of salt is associated with poor health outcomes, including cardiovascular disease 3 , kidney disease 4 , autoimmunity 5 , stomach cancer 6 , and dementia 7 . Hypertension is one of the important factors contributing to these diseases 3 , 8 . Although it is well established that high-salt-induced hypertension can lead to endothelial dysfunction 9 , vascular inflammation 10 , reduced arterial vasodilator capacity 11 , increased arterial stiffness 12 , and the promotion of vascular remodeling 13 , a detailed description of the heterogeneity and the relative contributions of different vascular cells in normal aortas and those in high-salt-induced hypertension is lacking.…”