Journal
ACS CHEMICAL NEUROSCIENCE
Volume 11, Issue 19, Pages 2978-2988Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00029
Keywords
Stress-induced hypertension; Toll-like receptor 4; angiotensin II; angiotensin II type 1 receptor; rostral ventrolateral medulla; cytokines
Funding
- Chinese National Natural Science Fund [31371155]
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This study aimed to investigate whether the proinflammatory and pressor effects of endogenous angiotensin II (AngII) are mediated by binding to the AngII type 1 receptor (AT(1)R) and subsequently activating central Toll-like receptor 4 (TLR4) in the rostral ventrolateral medulla (RVLM) of stress-induced hypertensive rats (SIHR). The stress-induced hypertension (SIH) model was established by random electric foot shocks combined with noise stimulation. Mean arterial pressure, heart rate, plasma norepinephrine, and RVLM AngII and TLR4 increased in a time-dependent manner in SIHR. Pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta)), myeloid differentiation factor 88 (MyD88), and nuclear factor (NF)-kappa B also increased, while anti-inflammatory cytokine IL-10 decreased in the RVLM of SIHR. These changes were attenuated by 14-day intra-cerebroventricular (ICV) infusion of VIPER (a TLR4 inhibitor) or candesartan (an AT(1)R antagonist). Both TLR4 and AT(1)R were expressed in the neurons and microglia in the RVLM of SIHR. Candesartan attenuated the expression of TLR4 in the RVLM of SIHR. This study demonstrated that endogenous AngII may activate AT(1)R to upregulate LR4/MyD88/NF-kappa B signaling and subsequently trigger an inflammatory response in the RVLM of SIHR, which in turn enhanced sympathetic activity and increased blood pressure.
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