Upregulation of AT1 Receptor Mediates a Pressor Effect Through ROS-SAPK/JNK Signaling in Glutamatergic Neurons of Rostral Ventrolateral Medulla in Rats With Stress-Induced Hypertension.

Danian Zhu,Shulan Ma,Hongyu Yang,Linlin Shen,Jijiang Wang,Yanlei Xin,Liping Jiang,Xuan Zhou,Jin Wang,Ruijuan Guan

doi:10.3389/fphys.2018.01860

Danian Zhu, Shulan Ma + Show 8 more

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https://doi.org/10.3389/fphys.2018.01860

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Journal: Frontiers in physiology	Publication Date: Jan 8, 2019
Citations: 15	License type: CC BY 4.0

Affiliation: Fudan University

Abstract

The present study examined whether angiotensin II (Ang II) mediates the pressor effect through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS)-mitogen-activated protein kinase (MAPK) signaling in the glutamatergic neurons of the rostral ventrolateral medulla (RVLM) in stress-induced hypertensive rats (SIHR). The SIHR model was established using electric foot-shocks combined with noises for 15 days. We observed that Ang II type 1 receptor (AT1R) and the glutamatergic neurons co-localized in the RVLM of SIHR. Furthermore, glutamate levels in the intermediolateral column of the spinal cord were higher in SIHR than in controls. Microinjection of Ang II into the RVLM of SIHR activated stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK), extracellular signal-regulated protein kinase (ERK) 1/2, and p38MAPK. Compared with controls, the activation of SAPK/JNK, ERK1/2, p38MAPK, and ROS in the RVLM were higher in SIHR, an effect that was blocked by an NADPH oxidase inhibitor (apocynin) and an AT1R antagonist (candesartan). RVLM microinjection of apocynin or a SAPK/JNK inhibitor (SP600125), but not an ERK1/2 inhibitor (U0126) or a p38MAPK inhibitor (SB203580), decreased AT1R mRNA and mean arterial blood pressure (MABP) in SIHR. The increase of AT1R protein expression and MABP was inhibited by intracerebroventricular infusion (ICV), for 14 days, of SP600125, but not U0126 or SB203580 in SIHR. We conclude that Ang II modulates the pressor effect through AT1R-dependent ROS-SAPK/JNK signaling in glutamatergic neurons in the RVLM of SIHR.

Highlights

Hypertension is a silent killer worldwide and an outcome of a convoluted interaction between genetic and environmental factors
To establish that the development of stressinduced hypertension (SIH) is associated with the actions of glutamatergic neurons in the rostral ventrolateral medulla (RVLM), we examined the concentration of amino acid neurotransmitters in the intermediolateral column (IML)
We examined the roles of AT1 R on cardiovascular modulation and the effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidasederived reactive oxygen species (ROS)-mitogen-activated protein kinase (MAPK) signaling in the glutamatergic neurons of the RVLM in stress-induced hypertensive rats (SIHR)

Summary

Introduction

Hypertension is a silent killer worldwide and an outcome of a convoluted interaction between genetic and environmental factors. Ang II can upregulate mRNA and protein expression of NADPH oxidase subunits and augment production of ROS (Hausding et al, 2013; Wakui et al, 2013; Ding et al, 2015; Minas et al, 2015). NADPH oxidase-derived ROS act as essential intracellular messengers to activate downstream signaling molecules, including mitogen-activated protein kinase (MAPK) and transcriptional factors (Zhang et al, 2007; Bae et al, 2011; Lassegue et al, 2012). A previous study demonstrated that chronic Ang II infusion elevated NADPH oxidase subunit protein expression, ROS production, as well as p38MAPK activation, leading to hypertension in Sprague Dawley rats (Bao et al, 2007)

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