Aldose reductase mediates endothelial cell dysfunction induced by high uric acid concentrations

Cell Communication and Signaling

Research

Quan Hong¹  Di Wu¹  Liyuan Wang¹  Xiangmei Chen¹  Guangyan Cai¹  Shaoyuan Cui¹  Zhe Feng¹  Yang Lv¹  Zhiyong Huang²  Wenzhen Xiao³  Xueguang Zhang³ 

[1] Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, 100853, Beijing, People’s Republic of China;Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, 100853, Beijing, People’s Republic of China;Department of Nephrology, The 175th Hospital of PLA, 36300, Zhangzhou Fujian, People’s Republic of China;Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;

关键词: Aldose reductase;    Endothelial cell dysfunction;    Uric acid;    Reactive oxygen species;    Hyperuricemia;    CKD;   

DOI  :  10.1186/s12964-016-0158-6

 received in 2016-01-21, accepted in 2016-12-20,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundUric acid (UA) is an antioxidant found in human serum. However, high UA levels may also have pro-oxidant functions. According to previous research, aldose reductase (AR) plays a vital role in the oxidative stress-related complications of diabetes. We sought to determine the mechanism by which UA becomes deleterious at high concentrations as well as the effect of AR in this process.MethodEndothelial cells were divided into three groups cultured without UA or with 300 μM or 600 μM UA. The levels of total reactive oxygen species (ROS), of four ROS components, and of NO and NOX4 expression were measured. Changes in the above molecules were detected upon inhibiting NOX4 or AR, and serum H2O2 and vWF levels were measured in vivo.ResultsIncreased AR expression in high UA-treated endothelial cells enhanced ROS production by activating NADPH oxidase. These effects were blocked by the AR inhibitor epalrestat. 300 μM UA decreased the levels of the three major reactive oxygen species (ROS) components: O2•-, •OH, and 1O2. However, when the UA concentration was increased, both O2•- levels and downstream H2O2 production significantly increased. Finally, an AR inhibitor reduced H2O2 production in hyperuricemic mice and protected endothelial cell function.ConclusionsOur findings indicate that inhibiting AR or degrading H2O2 could protect endothelial function and maintain the antioxidant activities of UA. These findings provide new insight into the role of UA in chronic kidney disease.

【 授权许可】

CC BY   
© The Author(s). 2017