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

摘要

Background 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. Method 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 H₂O₂ and vWF levels were measured in vivo. Results 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, 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. Conclusions Our 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.