2. Academic Validation
  3. Microglial activation and toll-like receptor 4-Dependent regulation of angiotensin II type I receptor-mu-opioid receptor 1 heterodimerization and hypertension in fructose-fed rats

Microglial activation and toll-like receptor 4-Dependent regulation of angiotensin II type I receptor-mu-opioid receptor 1 heterodimerization and hypertension in fructose-fed rats

  • Eur J Pharmacol. 2023 Nov 21:176171. doi: 10.1016/j.ejphar.2023.176171.
Chiu-Yi Ho 1,  Gwo-Ching Sun 2,  Yu-Te Lin 3,  Tzyy-Yue Wong 4,  Michael Hsiao 5,  Ching-Jiunn Tseng 6,  Pei-Wen Cheng 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.
  • 2 Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan; School of Medicine, National Defense Medicine Center, Taipei, Taiwan.
  • 3 Section of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung 81300, Taiwan; Center for Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung 81300, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
  • 4 Cross College Elite Program, National Cheng Kung University, Tainan 70101, Taiwan.
  • 5 Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan; Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan.
  • 6 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.
  • 7 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan. Electronic address: pwcheng@vghks.gov.tw.
PMID: 37996009 DOI: 10.1016/j.ejphar.2023.176171
Abstract

Our previous study reported that the heterodimer of Angiotensin II Type I Receptor (AT1R) and Mu-Opioid Receptor 1 (MOR1) involves Nitric Oxide (NO) reduction which leads to elevation of blood pressure. Secondly, we showed that Toll-like Receptor 4 (TLR4) may be involved in the heterodimerization of AT1R and MOR1 in the brainstem Nucleus Tractus Solitarii (NTS), which regulates systemic blood pressure and gastric nitric oxide through the Insulin pathway. Here, we investigated the role of microglial activation and TLR4 in the heterodimerization of AT1R and MOR1. Hypertensive rats were established after four weeks of fructose consumption. SBP of rats was measured using non-invasive blood pressure method. PLA technique was utilized to determine protein-protein interaction in the nucleus tractus solitarii. Results showed that the level of MOR-1 and AT1R was induced significantly in the fructose group compared with control. PLA signal potentially showed that AT1R and MOR1 were formed in the nucleus tractus solitarii after fructose consumption. Meanwhile, the innate immune cell in the CNS microglia was observed in the nucleus tractus solitarii using biomarkers and was activated. TLR4 Inhibitor CLI-095, was administered to Animals to suppress the neuroinflammation and microglial activation. CLI-095 treatment reduced the heterodimer formation of AT1R and MOR1 and restored nitric oxide production in the nucleus tractus solitarii. These findings imply that TLR4-primed neuroinflammation involves formation of heterodimers AT1R and MOR1 in the nucleus tractus solitarii which leads to increase in systemic blood pressure.

Keywords

HMGB1; Hypertension; Neuroinflammation; Nucleus tractus solitarii; TLR4.

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