1 Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of the Ministry of Education, Xi’an Jiaotong University, Xi’an 710061, China

2 Department of Cardiovascular Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China

3 Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China

4 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China

Abstract 

Toll-like receptor 4 (TLR4) and cellular Src (c-Src) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-Src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-Src, while microinjection of a c-Src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a long-term high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-Src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen species. Therefore, inhibiting central c-Src activity may be a new target for treating hypertension.

Keywords

Toll-like receptor 4; Cellular Src; Inflammatory cytokines; Oxidative stress; Hypothalamic paraventricular nucleus; Salt-induced hypertension 

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