title: Aldose reductase mediates endothelial cell dysfunction induced by high uric acid concentrations.
abstract: Uric 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.
  
  
  
  Endothelial 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 H2O2and vWF levels were measured in vivo.
  
  
  
  Increased 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, and1O2. However, when the UA concentration was increased, both O2•- levels and downstream H2O2production significantly increased. Finally, an AR inhibitor reduced H2O2production in hyperuricemic mice and protected endothelial cell function.
  
  
  
  Our findings indicate that inhibiting AR or degrading H2O2could protect endothelial function and maintain the antioxidant activities of UA. These findings provide new insight into the role of UA in chronic kidney disease.
authors.affiliation: 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, Beijing, 100853, People's Republic of China.|Department of Nephrology, The 175th Hospital of PLA, Zhangzhou Fujian, 36300, People's Republic of China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Cui
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lv
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Guangyan
authors.initials: G
authors.lastname: Cai
authors.affiliation: 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, Beijing, 100853, People's Republic of China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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, Beijing, 100853, People's Republic of China. wudi@301hospital.com.cn.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D033461:Hyperuricemia / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053778:Thiazolidines; C070295:catalase-polyethylene glycol; D014527:Uric Acid; D009569:Nitric Oxide; D011092:Polyethylene Glycols; C038131:epalrestat; D012236:Rhodanine; D006861:Hydrogen Peroxide; D000449:Aldehyde Reductase; D002374:Catalase; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Aldose reductase; CKD; Endothelial cell dysfunction; Hyperuricemia; Reactive oxygen species; Uric acid