μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System

Opioids, a kind of peptide hormone involved in the development of hypertension, cause systemic and cerebral inflammation, and affects regions of the brain that are important for blood pressure (BP) control. A cause-and-effect relationship exists between hypertension and inflammation; however, the ro...

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Autores principales:	Gwo-Ching Sun, Jockey Tse, Yung-Ho Hsu, Chiu-Yi Ho, Ching-Jiunn Tseng, Pei-Wen Cheng
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	angiotensin II type 1 receptor (AT1R) hypertension heterodimer toll like receptor 4 nucleus tractus solitarii opioids Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/deb1e3ed2ce64487b8887dc3d3e167af
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spelling	oai:doaj.org-article:deb1e3ed2ce64487b8887dc3d3e167af2021-11-25T16:28:33Zμ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System10.3390/antiox101117842076-3921https://doaj.org/article/deb1e3ed2ce64487b8887dc3d3e167af2021-11-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1784https://doaj.org/toc/2076-3921Opioids, a kind of peptide hormone involved in the development of hypertension, cause systemic and cerebral inflammation, and affects regions of the brain that are important for blood pressure (BP) control. A cause-and-effect relationship exists between hypertension and inflammation; however, the role of blood pressure in cerebral inflammation is not clear. Evidence showed that AT1R and μOR heterodimers’ formation in the NTS might lead to the progression of hypertension. In this study, we investigated the formation of the μOR/AT1R heterodimer, determined its correlation with μORs level in the NTS, and explored the role of TLR4-dependent inflammation in the development of hypertension. Results showed that Ang II increased superoxide and Iba-1 (microgliosis marker: ionized calcium-binding adaptor molecule (1) levels in the NTS of spontaneously hypertensive rats (SHRs). The AT1R II inhibitor, losartan, significantly decreased BP and abolished superoxide, Iba-1, TLR4 expression induced by Ang II. Furthermore, losartan significantly increased nNsOS<sup>S1416</sup> phosphorylation. Administration of a μOR agonist or antagonist in the NTS of WKY and SHRs increased endogenous μ-opioids, triggered the formation of μOR/AT1R heterodimers and the TLR4-dependent inflammatory pathway, and attenuated the effect of depressor nitric oxide (NO). These results imply an important link between neurotoxicity and superoxides wherein abnormal increases in NTS endogenous μ-opioids promote the interaction between Ang II and μOR, the binding of Ang II to AT1R, and the activation of microglia. In addition, the interaction between Ang II and μOR enhanced the formation of the AT1R and μOR heterodimers, and inactivated nNOS-derived NO, leading to the development of progressive hypertension.Gwo-Ching SunJockey TseYung-Ho HsuChiu-Yi HoChing-Jiunn TsengPei-Wen ChengMDPI AGarticleangiotensin II type 1 receptor (AT1R)hypertensionheterodimertoll like receptor 4nucleus tractus solitariiopioidsTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1784, p 1784 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	angiotensin II type 1 receptor (AT1R) hypertension heterodimer toll like receptor 4 nucleus tractus solitarii opioids Therapeutics. Pharmacology RM1-950
spellingShingle	angiotensin II type 1 receptor (AT1R) hypertension heterodimer toll like receptor 4 nucleus tractus solitarii opioids Therapeutics. Pharmacology RM1-950 Gwo-Ching Sun Jockey Tse Yung-Ho Hsu Chiu-Yi Ho Ching-Jiunn Tseng Pei-Wen Cheng μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System
description	Opioids, a kind of peptide hormone involved in the development of hypertension, cause systemic and cerebral inflammation, and affects regions of the brain that are important for blood pressure (BP) control. A cause-and-effect relationship exists between hypertension and inflammation; however, the role of blood pressure in cerebral inflammation is not clear. Evidence showed that AT1R and μOR heterodimers’ formation in the NTS might lead to the progression of hypertension. In this study, we investigated the formation of the μOR/AT1R heterodimer, determined its correlation with μORs level in the NTS, and explored the role of TLR4-dependent inflammation in the development of hypertension. Results showed that Ang II increased superoxide and Iba-1 (microgliosis marker: ionized calcium-binding adaptor molecule (1) levels in the NTS of spontaneously hypertensive rats (SHRs). The AT1R II inhibitor, losartan, significantly decreased BP and abolished superoxide, Iba-1, TLR4 expression induced by Ang II. Furthermore, losartan significantly increased nNsOS<sup>S1416</sup> phosphorylation. Administration of a μOR agonist or antagonist in the NTS of WKY and SHRs increased endogenous μ-opioids, triggered the formation of μOR/AT1R heterodimers and the TLR4-dependent inflammatory pathway, and attenuated the effect of depressor nitric oxide (NO). These results imply an important link between neurotoxicity and superoxides wherein abnormal increases in NTS endogenous μ-opioids promote the interaction between Ang II and μOR, the binding of Ang II to AT1R, and the activation of microglia. In addition, the interaction between Ang II and μOR enhanced the formation of the AT1R and μOR heterodimers, and inactivated nNOS-derived NO, leading to the development of progressive hypertension.
format	article
author	Gwo-Ching Sun Jockey Tse Yung-Ho Hsu Chiu-Yi Ho Ching-Jiunn Tseng Pei-Wen Cheng
author_facet	Gwo-Ching Sun Jockey Tse Yung-Ho Hsu Chiu-Yi Ho Ching-Jiunn Tseng Pei-Wen Cheng
author_sort	Gwo-Ching Sun
title	μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System
title_short	μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System
title_full	μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System
title_fullStr	μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System
title_full_unstemmed	μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System
title_sort	μ-opioid receptor-mediated at1r–tlr4 crosstalk promotes microglial activation to modulate blood pressure control in the central nervous system
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/deb1e3ed2ce64487b8887dc3d3e167af
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μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System

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