The effects of hyperuricemia on endothelial cells are mediated via GLUT9 and the JAK2/STAT3 pathway

Qian Nie,Zhimei Zhang,Chao Wang,Xuemei Zhang,Miaomiao Liu,Guangyao Song

doi:10.1007/s11033-021-06840-w

Qian Nie, Zhimei Zhang + Show 4 more

Open Access

https://doi.org/10.1007/s11033-021-06840-w

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Abstract

BackgroundUric acid (UA) transporters mediate the uptake and outflow of UA, and are greatly involved in the control of UA concentrations. Glucose transporter 9 (GLUT9), one of the UA transporters, has been confirmed to be expressed in human umbilical vein endothelial cells (HUVECs). This study aimed to characterize GLUT9’s effect on intracellular UA accumulation in HUVECs in a high-UA environment and to explore the mechanism of cellular dysfunction.Methods and resultsHUVECs were treated with UA to establish a model of cellular dysfunction. Then, UA uptake, GLUT9 expression and endothelial nitric oxide synthase (eNOS) and reactive oxygen species (ROS) amounts were measured. UA uptake was concentration- and time-dependent, and UA treatment significantly reduced nitric oxide (NO) levels and eNOS activity. UA also upregulated pro-inflammatory molecules and GLUT9, and increased intracellular ROS amounts in HUVECs. GLUT9 knockdown reduced UA uptake and ROS content, but antioxidant treatment did not reduce GLUT9 expression. To assess the function of JAK2/STAT3 signaling, HUVECs were treated with UA, and the phosphorylation levels of JAK2, STAT3, IL-6 and SOCS3 were increased by a high concentration of UA. In addition, GLUT9 knockdown reduced the phosphorylation of JAK2/STAT3 intermediates and increased p-eNOS amounts.ConclusionsGLUT9 mediated the effects of high UA levels on HUVECs by increasing the cellular uptake of UA, activating JAK2/STAT3 signaling, and reduced the production of active eNOS and NO in HUVECs.

Highlights

Uric acid (UA) constitutes the end-product of primates’ metabolic reactions transforming purine nucleosides
We hypothesized that the balance between intracellular and extracellular UA amounts is regulated by uric acid transport, which should involve the role of Glucose transporter 9 (GLUT9)
human umbilical vein endothelial cells (HUVECs) were treated with high UA concentrations to mimic hyperuricemia, and the roles played by the UA transporter GLUT9 in the deleterious effects of UA on HUVECs were evaluated, attempting to explore the molecular mechanisms involved

Summary

Introduction

Uric acid (UA) constitutes the end-product of primates’ metabolic reactions transforming purine nucleosides. UA transporters, including URAT1, GLUT9 and breast cancer resistance protein (BCRP), mediate UA uptake and outflow, greatly regulating UA concentrations in the body [9, 10]. UA transporters increase its intracellular accumulation, thereby promoting cell dysfunction To test this hypothesis, the effects of high UA concentration on UA’s intracellular accumulation and GLUT9 levels in HUVECs were examined, exploring the mechanism by which UA induces cell damage. UA uptake, GLUT9 expression and endothelial nitric oxide synthase (eNOS) and reactive oxygen species (ROS) amounts were measured. Conclusions GLUT9 mediated the effects of high UA levels on HUVECs by increasing the cellular uptake of UA, activating JAK2/STAT3 signaling, and reduced the production of active eNOS and NO in HUVECs

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