Abstract
Excessive dietary salt intake induces neuroinflammation and oxidative stress in the brain, which lead to sympathetic excitation, contributing to hypertension. However, the underlying mechanisms remain elusive. Accumulating evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite, is implicated in the pathogenesis of multiple cardiovascular diseases. The present study sought to determine whether central TMAO is elevated and associated with neuroinflammation and oxidative stress in the brain after long-term high salt (HS) diet intake and, if so, whether inhibition of TMAO generation ameliorates HS-induced sympathetic excitation and hypertension. Sprague–Dawley rats were fed either a HS diet or a normal salt (NS) diet and simultaneously treated with vehicle (VEH) or 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) for 8 weeks. HS + VEH rats, compared with NS + VEH rats, had elevated TMAO in plasma and cerebrospinal fluid (CSF), increased blood pressure (BP), and increased sympathetic drive as indicated by the BP response to ganglionic blockade and plasma norepinephrine levels. HS-induced these changes were attenuated by DMB, which significantly reduced TMAO in plasma and CSF. Neuroinflammation as assessed by proinflammatory cytokine expression and NF-κB activity and microglial activity, and oxidative stress as measured by NAD(P)H oxidase subunit expression and NAD(P)H activity and reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) were increased in HS + VEH rats but were decreased by DMB. DMB had no effects on above measured parameters in NS rats. The results suggest that long-term HS diet intake causes elevation in TMAO in the circulation and brain, which is associated with increased neuroinflammation and oxidative stress in the PVN, an important cardiovascular regulatory center. Inhibition of TMAO generation ameliorates HS-induced sympathetic excitation and hypertension by reducing neuroinflammation and oxidative stress in the PVN.
Highlights
Hypertension is one of the most important risk factors for cardiovascular disease, which is the leading cause of mortality globally (O’Donnell et al, 2015; Grillo et al, 2019)
After 1-week acclimation, rats were randomly divided into 4 groups: 1) normal salt diet (NS, 0.5% NaCl) group treated with vehicle (VEH, tap water) (NS + VEH, n = 30 rats); 2) NS group treated with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of TMA formation), (NS + DMB, n = 30 rats); 3) high salt diet (HS, 8% NaCl) group treated with VEH (HS + VEH, n = 30 rats); 4) HS group treated with DMB (HS + DMB, n = 30 rats)
The major findings of this study are that HS feeding increases TMAO in the periphery and in the brain, which is associated with elevated neuroinflammation and oxidative stress in the paraventricular nucleus (PVN); inhibition of TMAO production reduces neuroinflammation and oxidative stress in the PVN, ameliorates sympathetic excitation and prevents hypertension in rats fed a HS diet
Summary
Hypertension is one of the most important risk factors for cardiovascular disease, which is the leading cause of mortality globally (O’Donnell et al, 2015; Grillo et al, 2019). There is considerable evidence that activation of the sympathetic nervous system plays an important role in the pathogenesis of several cardiovascular diseases, including salt-induced hypertension (Campese et al, 1982; Su et al, 2016; Liang et al, 2017; Jiang et al, 2018). Excess dietary salt intake has been shown to increase neuroinflammation and oxidative stress in the PVN, which augment sympathetic nerve activity, contributing to the development and maintenance of hypertension (Liang et al, 2017; Jiang et al, 2018; Yu et al, 2019). Pharmacological interventions that inhibit neuroinflammation and oxidative stress in the PVN reduce sympathetic activation and attenuate hypertension in animals fed a high salt (HS) diet (Liang et al, 2017; Yu et al, 2019). The precise mechanisms by which high salt diet induces neuroinflammation and oxidative stress in the PVN remain unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
