The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling
Brain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can act...
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doaj-5b2365708b244db3947803c3b4a3435a2020-11-24T21:53:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-04-011010.3389/fphar.2019.00318439426The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin SignalingXiaoxue Gong0Hui Hu1Yi Qiao2Pengfei Xu3Mengqi Yang4Ruili Dang5Wenxiu Han6Yujin Guo7Dan Chen8Pei Jiang9Institute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaDepartment of Cardiology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaDepartment of Public Health, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaInstitute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, ChinaBrain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can activate each other, forming a positive feedback loop that would result in exacerbated unwanted tissue damage. To further examine the interrelationship among insulin signaling, neuroinflammation and RAS in the brain, the effect of repeated lipopolysaccharide (LPS) exposure and co-treatment with the angiotensin II (Ang II) receptor type 1 (AT1) blocker, candesartan (Cand), on anxiety and depression-like behaviors, RAS, neuroinflammation and insulin signaling was explored. Our results demonstrated that prolonged LPS challenge successfully induced the rats into anxiety and depression-like state, accompanied with significant neural apoptosis and neuroinflammation. LPS also activated RAS as evidenced by the enhanced angiotensin converting enzyme (ACE) expression, Ang II generation and AT1 expression. However, blocking the activated RAS with Cand co-treatment conferred neurobehavioral protective properties. The AT1 blocker markedly ameliorated the microglial activation, the enhanced gene expression of the proinflammatory cytokines and the overactivated NF-κB signaling. In addition, Cand also mitigated the LPS-induced disturbance of insulin signaling with the normalized phosphorylation of serine 307 and tyrosine 896 of insulin receptor substrate-1 (IRS-1). Collectively, the present study, for the first time, provided the direct evidence indicating that the inflammatory condition may interact with RAS to impede brain insulin pathway, resulting in neurobehavioral damage, and inhibiting RAS seems to be a promising strategy to block the cross-talk and cut off the vicious cycle between RAS and immune system.https://www.frontiersin.org/article/10.3389/fphar.2019.00318/fulllipopolysaccharidedepressionrenin-angiotensin systeminflammationinsulin pathway |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaoxue Gong Hui Hu Yi Qiao Pengfei Xu Mengqi Yang Ruili Dang Wenxiu Han Yujin Guo Dan Chen Pei Jiang |
spellingShingle |
Xiaoxue Gong Hui Hu Yi Qiao Pengfei Xu Mengqi Yang Ruili Dang Wenxiu Han Yujin Guo Dan Chen Pei Jiang The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling Frontiers in Pharmacology lipopolysaccharide depression renin-angiotensin system inflammation insulin pathway |
author_facet |
Xiaoxue Gong Hui Hu Yi Qiao Pengfei Xu Mengqi Yang Ruili Dang Wenxiu Han Yujin Guo Dan Chen Pei Jiang |
author_sort |
Xiaoxue Gong |
title |
The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling |
title_short |
The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling |
title_full |
The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling |
title_fullStr |
The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling |
title_full_unstemmed |
The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling |
title_sort |
involvement of renin-angiotensin system in lipopolysaccharide-induced behavioral changes, neuroinflammation, and disturbed insulin signaling |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2019-04-01 |
description |
Brain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can activate each other, forming a positive feedback loop that would result in exacerbated unwanted tissue damage. To further examine the interrelationship among insulin signaling, neuroinflammation and RAS in the brain, the effect of repeated lipopolysaccharide (LPS) exposure and co-treatment with the angiotensin II (Ang II) receptor type 1 (AT1) blocker, candesartan (Cand), on anxiety and depression-like behaviors, RAS, neuroinflammation and insulin signaling was explored. Our results demonstrated that prolonged LPS challenge successfully induced the rats into anxiety and depression-like state, accompanied with significant neural apoptosis and neuroinflammation. LPS also activated RAS as evidenced by the enhanced angiotensin converting enzyme (ACE) expression, Ang II generation and AT1 expression. However, blocking the activated RAS with Cand co-treatment conferred neurobehavioral protective properties. The AT1 blocker markedly ameliorated the microglial activation, the enhanced gene expression of the proinflammatory cytokines and the overactivated NF-κB signaling. In addition, Cand also mitigated the LPS-induced disturbance of insulin signaling with the normalized phosphorylation of serine 307 and tyrosine 896 of insulin receptor substrate-1 (IRS-1). Collectively, the present study, for the first time, provided the direct evidence indicating that the inflammatory condition may interact with RAS to impede brain insulin pathway, resulting in neurobehavioral damage, and inhibiting RAS seems to be a promising strategy to block the cross-talk and cut off the vicious cycle between RAS and immune system. |
topic |
lipopolysaccharide depression renin-angiotensin system inflammation insulin pathway |
url |
https://www.frontiersin.org/article/10.3389/fphar.2019.00318/full |
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