AT1R/GSK-3/mTOR Signaling Pathway Involved in Angiotensin II-Induced Neuronal Apoptosis After HIE Both In Vitro and In Vivo

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2021 Jan 11

PMID 33425219

Citations 6

Authors

Wei Si

Banghui Li

Cameron Lenahan

Shirong Li

Ran Gu

Hao Qu

Lu Wang

Jiapeng Liu

Tian Tian

Qian Wang

XikeWang

Xiao Hu

Gang Zuo

Affiliations

Soon will be listed here.

Abstract

Objective: The focus of the present study is to evaluate the effects of Angiotensin II (Ang II) on neuronal apoptosis after HIE and the potential underlying mechanisms.

Methods: Primary neonatal rat cortical neurons were used to study the oxygen-glucose deprivation (OGD) cell model. The expressions of Ang II, AT1R, GSK-3, p-GSK-3, mTOR, p-mTOR, Bax, Bcl-2, and cleaved caspase-3 were detected via western blot. IF and flow cytometry were used to evaluate neuronal apoptosis. Hypoxic-ischemic encephalopathy (HIE) was established to evaluate the therapeutic effects of Ang II in vivo. Cerebral infarction areas were detected by 2,3,5-Triphenyltetrazolium chloride staining. The righting and geotaxis reflexes were also recorded. In addition, Fluoro-Jade C staining and TUNEL staining were performed to evaluate neuronal degeneration and apoptosis.

Results: Ang II significantly increased the rate of neuronal apoptosis, upregulated the expression of cleaved caspase-3, and downregulated Bcl-2/Bax ratio after OGD insult. For vivo assay, the expressions of endogenous Ang II and AT1R gradually increased and peaked at 24 h after HIE. Ang II increased NeuN-positive AT1R cell expression. In addition, Ang II increased the area of cerebral infarction, promoted neuronal degeneration and apoptosis, aggravated neurological deficits on righting and geotaxis reflexes, and was accompanied by increased expressions of phosphorylated GSK-3 and mTOR. The application of valsartan (Ang II inhibitor) or SB216763 (GSK-3 inhibitor) reversed these phenomena triggered by Ang II following HIE.

Conclusion: Ang II increased neuronal apoptosis through the AT1R/GSK-3/mTOR signaling pathway after experimental HIE both in vitro and in vivo, and Ang II may serve as a novel therapeutic target to ameliorate brain injury after HIE.

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