Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice

Type 2 diabetes (T2D)-related neurological complication is the risk factor for neurodegenerative disorders. The pathological changes from T2D-caused blood–brain barrier (BBB) dysfunction plays a critical role in developing neurodegeneration. The hyper-activation of the Angiotensin II type 1 receptor...

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Autores principales:	Longxue Cai, Wenfeng Li, Renqing Zeng, Zuohong Cao, Qicai Guo, Qi Huang, Xianfa Liu
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	valsartan blood-brain barrier (bbb) db/db mice human brain microvascular endothelial cells (hbmvecs) camp-responsive element-binding protein (creb) Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/19354ee41a994ffa90f4b8afb3875ce8
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spelling	oai:doaj.org-article:19354ee41a994ffa90f4b8afb3875ce82021-11-04T15:51:53ZValsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice2165-59792165-598710.1080/21655979.2021.1981799https://doaj.org/article/19354ee41a994ffa90f4b8afb3875ce82021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/21655979.2021.1981799https://doaj.org/toc/2165-5979https://doaj.org/toc/2165-5987Type 2 diabetes (T2D)-related neurological complication is the risk factor for neurodegenerative disorders. The pathological changes from T2D-caused blood–brain barrier (BBB) dysfunction plays a critical role in developing neurodegeneration. The hyper-activation of the Angiotensin II type 1 receptor (AT1R) in the brain is associated with neurovascular impairment. The AT1R antagonist Valsartan is commonly prescribed to control high blood pressure, heart failure, and diabetic kidney diseases. In this study, we investigated the beneficial effects of Valsartan in db/db diabetic mice and isolated brain endothelial cells. We showed that 2 weeks of Valsartan administration (30 mg/Kg body weight) mitigated the increased permeability of the brain-blood barrier and the reduction of gap junction proteins VE-Cadherin and Claudin 2. In human brain microvascular cells (HBMVECs), we found that Valsartan treatment ameliorated high glucose-induced hyperpermeability by measuring Dextran uptake and transendothelial electrical resistance (TEER). Furthermore, Valsartan treatment recovered high glucose-repressed endothelial VE-Cadherin and Claudin 2 expression. Moreover, Valsartan significantly suppressed the expressions of pro-inflammatory cytokines such as macrophage chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) against high glucose. Mechanistically, Valsartan ameliorated high glucose-repressed endothelial cAMP-responsive element-binding protein (CREB) signaling activation. The blockage of CREB activation by PKA inhibitor H89 abolished the action of Valsartan, suggesting its dependence on CREB signaling. In conclusion, Valsartan shows a neuroprotective effect in diabetic mice by ameliorating BBB dysfunction. These effects of Valsartan require cellular CREB signaling in brain endothelial cells.Longxue CaiWenfeng LiRenqing ZengZuohong CaoQicai GuoQi HuangXianfa LiuTaylor & Francis Grouparticlevalsartanblood-brain barrier (bbb)db/db micehuman brain microvascular endothelial cells (hbmvecs)camp-responsive element-binding protein (creb)BiotechnologyTP248.13-248.65ENBioengineered, Vol 12, Iss 1, Pp 9070-9080 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	valsartan blood-brain barrier (bbb) db/db mice human brain microvascular endothelial cells (hbmvecs) camp-responsive element-binding protein (creb) Biotechnology TP248.13-248.65
spellingShingle	valsartan blood-brain barrier (bbb) db/db mice human brain microvascular endothelial cells (hbmvecs) camp-responsive element-binding protein (creb) Biotechnology TP248.13-248.65 Longxue Cai Wenfeng Li Renqing Zeng Zuohong Cao Qicai Guo Qi Huang Xianfa Liu Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
description	Type 2 diabetes (T2D)-related neurological complication is the risk factor for neurodegenerative disorders. The pathological changes from T2D-caused blood–brain barrier (BBB) dysfunction plays a critical role in developing neurodegeneration. The hyper-activation of the Angiotensin II type 1 receptor (AT1R) in the brain is associated with neurovascular impairment. The AT1R antagonist Valsartan is commonly prescribed to control high blood pressure, heart failure, and diabetic kidney diseases. In this study, we investigated the beneficial effects of Valsartan in db/db diabetic mice and isolated brain endothelial cells. We showed that 2 weeks of Valsartan administration (30 mg/Kg body weight) mitigated the increased permeability of the brain-blood barrier and the reduction of gap junction proteins VE-Cadherin and Claudin 2. In human brain microvascular cells (HBMVECs), we found that Valsartan treatment ameliorated high glucose-induced hyperpermeability by measuring Dextran uptake and transendothelial electrical resistance (TEER). Furthermore, Valsartan treatment recovered high glucose-repressed endothelial VE-Cadherin and Claudin 2 expression. Moreover, Valsartan significantly suppressed the expressions of pro-inflammatory cytokines such as macrophage chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) against high glucose. Mechanistically, Valsartan ameliorated high glucose-repressed endothelial cAMP-responsive element-binding protein (CREB) signaling activation. The blockage of CREB activation by PKA inhibitor H89 abolished the action of Valsartan, suggesting its dependence on CREB signaling. In conclusion, Valsartan shows a neuroprotective effect in diabetic mice by ameliorating BBB dysfunction. These effects of Valsartan require cellular CREB signaling in brain endothelial cells.
format	article
author	Longxue Cai Wenfeng Li Renqing Zeng Zuohong Cao Qicai Guo Qi Huang Xianfa Liu
author_facet	Longxue Cai Wenfeng Li Renqing Zeng Zuohong Cao Qicai Guo Qi Huang Xianfa Liu
author_sort	Longxue Cai
title	Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
title_short	Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
title_full	Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
title_fullStr	Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
title_full_unstemmed	Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
title_sort	valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/19354ee41a994ffa90f4b8afb3875ce8
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Valsartan alleviates the blood–brain barrier dysfunction in db/db diabetic mice

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