Hyperoside Downregulates the Receptor for Advanced Glycation End Products (RAGE) and Promotes Proliferation in ECV304 Cells via the c-Jun N-Terminal Kinases (JNK) Pathway Following Stimulation by Advanced Glycation End-Products In Vitro

Zhengyu Zhang,Yuxiao Zou,Sentai Liao,Weizhi Shen,Mosha Sethiel

doi:10.3390/ijms141122697

Abstract

Hyperoside is a major active constituent in many medicinal plants which are traditionally used in Chinese medicines for their neuroprotective, anti-inflammatory and antioxidative effects. The molecular mechanisms underlying these effects are unknown. In this study, quiescent ECV304 cells were treated in vitro with advanced glycation end products (AGEs) in the presence or absence of hyperoside. The results demonstrated that AGEs induced c-Jun N-terminal kinases (JNK) activation and apoptosis in ECV304 cells. Hyperoside inhibited these effects and promoted ECV304 cell proliferation. Furthermore, hyperoside significantly inhibited RAGE expression in AGE-stimulated ECV304 cells, whereas knockdown of RAGE inhibited AGE-induced JNK activation. These results suggested that AGEs may promote JNK activation, leading to viability inhibition of ECV304 cells via the RAGE signaling pathway. These effects could be inhibited by hyperoside. Our findings suggest a novel role for hyperoside in the treatment and prevention of diabetes.

Highlights

Hyperoside is a flavonoid compound mainly found in herbal plants which are traditionally used in Chinese medicines for their neuroprotective, anti-inflammatory, antioxidative and vascular protective effects
Our findings indicated that hyperoside may inhibit Jun N-terminal kinases (JNK) activation and promote ECV304 cell proliferation by downregulating receptor for AGE (RAGE)
There was a significant difference between cells treated with advanced glycation end products (AGEs) and hyperoside compared to those treated with AGEs alone (p < 0.05; Figure 1), indicating that hyperoside promoted cell viability

Summary

Introduction

Hyperoside is a flavonoid compound mainly found in herbal plants which are traditionally used in Chinese medicines for their neuroprotective, anti-inflammatory, antioxidative and vascular protective effects. Treatment with hyperoside has been found to attenuate endothelial cell damage induced by oxidative stress [1]. The binding of advanced glycation end products (AGE) to the receptor for AGE (RAGE) is known to deteriorate various cell functions and is implicated in the pathogenesis of diabetic vascular complications [3]. AGEs activate the RAGE gene through NF-kappaB (NF-κB) and Sp-1 in ECV304 cells, thereby enhancing AGE-RAGE interactions, which can lead to an exacerbation of diabetic microvasculopathy [4]. It is unclear whether hyperoside can inhibit apoptosis in ECV304 cells in response to AGEs

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Conclusion