Abstract
Accumulating evidence indicates that inflammation is implicated in hypertension. However, the role of brain proinflammatory cytokines (PICs) in salt sensitive hypertension remains to be determined. Thus, the objective of this study was to test the hypothesis that high salt (HS) diet increases PICs expression in the paraventricular nucleus (PVN) and leads to PVN neuronal activation. Eight-week-old male Dahl salt sensitive (Dahl S) rats, and age and sex matched normal Sprague Dawley (SD) rats were divided into two groups and fed with either a HS (4% NaCl) or normal salt (NS, 0.4% NaCl) diet for 5 consecutive weeks. HS diet induced hypertension and significantly increased cerebrospinal fluid (CSF) sodium concentration ([Na+]) in Dahl S rats, but not in normal SD rats. In addition, HS diet intake triggered increases in mRNA levels and immunoreactivities of PVN PICs including TNF-α, IL-6, and IL-1β, as well as Fra1, a chronic marker of neuronal activation, in Dahl S rats, but not in SD rats. Next, we investigated whether this increase in the expression of PVN PICs and Fra1 was induced by increased CSF [Na+]. Adult male SD rats were intracerebroventricular (ICV) infused with 8 μl of either hypertonic salt (4 μmol NaCl), mannitol (8 μmol, as osmolarity control), or isotonic salt (0.9% NaCl as vehicle control). Three hours following the ICV infusion, rats were euthanized and their PVN PICs expression was measured. The results showed that central administration of hypertonic saline in SD rats significantly increased the expression of PICs including TNF-α, IL-6, and IL-1β, as well as neuronal activation marker Fra1, compared to isotonic NaCl controls and osmolarity controls. Finally, we tested whether the increase in PICs expression occurred in neurons. Incubation of hypothalamic neurons with 10 mM NaCl in a culture medium for 6 h elicited significant increases in TNF-α, IL-6, and Fra1 mRNA levels. These observations, coupled with the important role of PICs in modulating neuronal activity and stimulating vasopressin release, suggest that HS intake induces an inflammatory state in the PVN, which, may in turn, augments sympathetic nerve activity and vasopressin secretion, contributing to the development of salt sensitive hypertension.
Highlights
Hypertension remains one of the most common diseases in the United States and it affects about 29% adult populations and more than 65% persons older than 60 years (Kovell et al, 2015)
high salt (HS) diet intake dramatically increased water intake and urine execration in both Dahl salt sensitive (Dahl S) rats and Sprague Dawley (SD) rats (Water intake, normal salt (NS): 23.9 ± 3.3 vs. HS: 58.4 ± 1.4 ml; urine output, NS: 14.5 ± 1.7 vs. HS: 42.6 ± 2.0 ml) compared to their NS intake controls (Figures 1A,B) In addition, in Dahl S rats, HS intake significantly increased mean arterial pressure (MAP) (NS: 122 ± 2 vs. HS: 153 ± 9 mmHg, P < 0.05), and cerebrospinal fluid (CSF) [Na+] (NS: 153.0 ± 1.3 vs. HS: 158.5 ± 1.1 mM, P < 0.05), but not significantly altered CSF osmolarity (NS: 316.3 ± 2.6 vs. HS: 321.8 ± 3.8 mOsm/L, P > 0.05) compared to Dahl S rats on a NS diet (Figures 1C,E,G). These changes in blood pressure and CSF [Na+] were specific to Dahl S rats as normal SD rats showed no significant changes in MAP (NS: 102 ± 3 vs. HS:107 ± 4 mmHg, P > 0.05), CSF [Na+] (NS: 155.2 ± 0.7 vs. HS: 153.9 ± 1.2 mM, P > 0.05), CSF osmolarity (NS: 310.8 ± 1.8 vs. HS: 315.8 ± 1.9 mOsm/L, P > 0.05) (Figures 1D,F,H). These results suggest that alteration of metabolism is not a major factor resulting in hypertension since normal SD rats increased water intake and urine excretion in response to HS diet but keep normal blood pressure
Eight-week-old male Dahl S rats and age and sex matched SD rats were divided into two groups and were fed either an HS or NS diet for 5 weeks
Summary
Hypertension remains one of the most common diseases in the United States and it affects about 29% adult populations and more than 65% persons older than 60 years (Kovell et al, 2015). While there are many contributing factors to hypertension including genetics and ethnicity, a major contributing factor to hypertension is diet (de Wardener et al, 2004). High dietary intake of sodium chloride (salt), especially prevalent in western cultures, has been identified as a major risk factor for the development of hypertension (de Wardener et al, 2004; Drenjancevic-Peric et al, 2011). Increased circulating levels of pro-inflammatory cytokines (PICs) including Tumor necrosis factor alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1 beta (IL-1β) have been noted in both human hypertension and animal models of hypertension (Dalekos et al, 1996, 1997; Liu et al, 1996). Injection of PICs such as TNF-α and IL-1β in the brain cardiovascular control areas of normal rats can dramatically increase blood pressure (Wei et al, 2015). The connection between high salt diet and changes in PICs in salt sensitive hypertension (SSHTN) has not been well established, especially in the central nervous system
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