ArticlePharmacological research2021
TLR4 and AT1R mediate blood-brain barrier disruption, neuroinflammation, and autonomic dysfunction in spontaneously hypertensive rats.
Article in Pharmacological research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 88 citations in OpenAlex.
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- Central Sympathetic Nerve Activation-Mediated Hypertension: Target Mechanisms and Multimodal Interventions-From Basic Research to Clinical Translation.International journal of molecular sciences · 2026Review
- Repeated TLR7 activation induces cell type- and brain region-specific transcriptome changes in male mice.Scientific reports · 2026Article
- The impact of inflammation, neuromodulation, and gut microbiota on developing cardiac fibrosis and hypertension.Cardiovascular research · 2026Review
- AT1R in Central Nervous System Disorders: Unveiling Novel Mechanisms and Therapeutic Avenues for Addiction.Addiction biology · 2026Review
- Ang II-mediated effects on BBB integrity in psychiatric and neurological disorders.Progress in neuro-psychopharmacology & biological psychiatry · 2026Review
- The brain-heart axis: effects of cardiovascular disease on the CNS and opportunities for central neuromodulation.Nature reviews. Neuroscience · 2026Review
- Microglial activation and RAS signaling: a dual-edged sword in neuroinflammation.American journal of physiology. Regulatory, integrative and comparative physiology · 2026Review
- Pyridostigmine Attenuated Placental Ischemia-Upregulated Paraventricular Nucleus TLR4-Associated Hypertension in Preeclamptic Rats.Molecular neurobiology · 2026Article
- Repurposing Renin-Angiotensin System Drugs for the Treatment of Audiovestibular Disorders.Journal of clinical medicine · 2026Review
- HSP60 Mediates NLRP3 Inflammasome-Dependent Microglial Pyroptosis Via the TLR4/MyD88/NF-κB Signaling Axis After Subarachnoid Hemorrhage.Inflammation · 2026Article
- Chunghyul-dan, a multi-botanical ethanol extract, improves collateral perfusion and neurovascular stability in permanent focal cerebral ischemia.Frontiers in pharmacology · 2026Article
- Insights into the molecular mechanism of neurological diseases and their pathophysiological responses.Archives of toxicology · 2025Review
- Impact of Hematopoietic CD14 on Oxidative Stress during Salt-Sensitive Hypertension and Kidney Injury.Journal of the American Society of Nephrology : JASN · 2025Article
- Targeting Kinin B1R Attenuates Hypertension Through AT1R-Dependent Mechanisms.Circulation research · 2025Article
- CX3CR1-TLR4 Axis as a Shared Neuroimmune Target in COVID-19 and Epilepsy: Integrative Transcriptomics and Gabapentin Repositioning.Biomedicines · 2025Article
- Chronic Copper Overload Triggers Inflammation in Mesenteric PVAT Alongside Changes in Renin-Angiotensin System-Related Pathways.Nutrients · 2025Article
- Losartan attenuates sex-dependent hypertension, neuroinflammation, and cognitive impairment in the aging male sprague-dawley rat.GeroScience · 2025Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Angiotensin II (AngII) is implicated in neuroinflammation, blood-brain barrier (BBB) disruption, and autonomic dysfunction in hypertension. We have previously shown that exogenous AngII stimulates Toll-like receptor 4 (TLR4) via AngII type 1 receptor (AT1R), inducing activation of hypothalamic microglia ex vivo, and that AngII-AT1R signaling is necessary for the loss of BBB integrity in spontaneously hypertensive rats (SHRs). Herein, we hypothesized that microglial TLR4 and AT1R signaling interactions represent a crucial mechanistic link between AngII-mediated neuroinflammation and BBB disruption, thereby contributing to sympathoexcitation in SHRs. Male SHRs were treated with TAK-242 (TLR4 inhibitor; 2 weeks), Losartan (AT1R inhibitor; 4 weeks), or vehicle, and age-matched to control Wistar Kyoto rats (WKYs). TLR4 and AT1R inhibitions normalized increased TLR4, interleukin-6, and tumor necrosis factor-α protein densities in SHR cardioregulatory nuclei (hypothalamic paraventricular nucleus [PVN], rostral ventrolateral medulla [RVLM], and nucleus tractus solitarius [NTS]), and abolished enhanced microglial activation. PVN, RVLM, and NTS BBB permeability analyses revealed complete restoration after TAK-242 treatment, whereas SHRs presented with elevated dye leakage. Mean arterial pressure was normalized in Losartan-treated SHRs, and attenuated with TLR4 inhibition. In conscious assessments, TLR4 blockade rescued SHR baroreflex sensitivity to vasoactive drugs, and reduced the SHR pressor response to ganglionic blockade to normal levels. These data suggest that TLR4 activation plays a substantial role in mediating a feed-forward pro-hypertensive cycle involving BBB disruption, neuroinflammation, and autonomic dysfunction, and that TLR4-specific therapeutic interventions may represent viable alternatives in the treatment of hypertension.
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