Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension.

Rahul B Dange,Ryoichi Teruyama,Deepmala Agarwal,Joseph Francis

doi:10.1186/s12974-015-0242-7

Rahul B Dange, Ryoichi Teruyama + Show 2 more

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https://doi.org/10.1186/s12974-015-0242-7

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Abstract

BackgroundDespite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis. Recent evidence suggests the role of toll-like receptor (TLR) 4 in various inflammatory diseases, including hypertension. The role of the brain in the initiation and progression of all forms of hypertension is well established, but the role of brain TLR4 in progression of hypertension has never been explored. Therefore, we investigated the role of TLR4 within the paraventricular nucleus (PVN; an important cardioregulatory center in the brain) in an animal model of human essential hypertension. We hypothesized that a TLR4 blockade within the PVN causes a reduction in mean arterial blood pressure (MAP), inflammatory cytokines and sympathetic drive in hypertensive animals.MethodsSpontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were administered either a specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide in their PVN for 14 days. MAP was recorded continuously by radiotelemetry. PVN and blood were collected for the measurement of pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β), anti-inflammatory cytokine IL-10, inducible nitric oxide synthase (iNOS), TLR4, nuclear factor (NF) κB activity and plasma norepinephrine (NE) and high mobility group box (HMGB)1 expression, respectively.ResultsHypertensive rats exhibited significantly higher levels of TLR4 in the PVN. TLR4 inhibition within the PVN attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, iNOS levels, and NFκB activity in SHR but not in WKY rats. These results were associated with a reduction in plasma NE and HMGB1 levels and an increase in IL-10 levels in SHR.ConclusionsThis study demonstrates that TLR4 upregulation in PVN plays an important role in hypertensive response. Our results provide mechanistic evidence that hypertensive response in SHR are mediated, at least in part, by TLR4 in the PVN and that inhibition of TLR4 within the PVN attenuates blood pressure and improves inflammation, possibly via reduction in sympathetic activity.

Highlights

Despite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis
Toll-like receptor 4 is highly expressed in the neurons and microglia of paraventricular nucleus in hypertensive rats Immunofluorescence staining of the PVN sections showed that TLR4 is highly expressed in Spontaneously hypertensive rats (SHR) + control peptide (CP) groups when compared to Wistar Kyoto (WKY) + CP (Figures 1, 2 and 3)
Toll-life receptor 4 blockade altered expression of pro- and anti-inflammatory cytokines in hypertensive rats To determine the effect of TLR4 blockade within the PVN on inflammatoy response in hypertension, we examined the levels of pro-inflammatory cytokines (PICs), Tumor necrosis factor-alpha (TNF-α) and Interleukin-1 beta (IL-1β) mRNA (Figure 6A-B) and protein (Figure 6 C-D) levels in the PVN by real time room temperature (RT) PCR and western immunoblot, respectively

Summary

Introduction

Despite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis. Recent evidence suggests the role of toll-like receptor (TLR) 4 in various inflammatory diseases, including hypertension. We investigated the role of TLR4 within the paraventricular nucleus (PVN; an important cardioregulatory center in the brain) in an animal model of human essential hypertension. We hypothesized that a TLR4 blockade within the PVN causes a reduction in mean arterial blood pressure (MAP), inflammatory cytokines and sympathetic drive in hypertensive animals. In the CNS, the brain is the central organ playing an important in fluid homeostasis and sympathetic regulation of blood pressure (BP). Unlike previous studies indicating the role played by the brain in late stage hypertensive disease, a growing body of evidence suggests the role of the brain in the initiation and progression of all forms of hypertension including essential hypertension [11]

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