Role Of Aldose Reductase In Endothelial Cells Oxidative Damage By High Uric Acid

Background: Uric acid is a powerful antioxidant that scavenges singlet oxygen(1O2), oxygen radicals, and peroxynitrite and chelates transition metals, to reduce, forinstance, iron ion–mediated ascorbic acid oxidation. It is estimated thatapproximately50%of serum antioxidant activity is contributed by uric acid. However,in vitro and cellular studies have demonstrated that uric acid may also be apro-oxidant depending on its chemical microenvironment. There is strongepidemiological evidence that the prevalence of gout and hyperuricemia is on theincrease worldwide. A vast literature overwhelmingly shows that, a high level of uricacid is strongly associated with and in many cases predicts，development ofhypertension, visceral obesity, insulin resistance, dyslipidemia, diabetes type II,kidney disease, and cardiovascular events. How it can become deleterious at highconcentrations?Objective: The aim of this study is to explore the pathway of endothelial injurycaused by high uric acid.Methods: Human umbilical vein endothelial cells were cultured and stimulatedwith uric acid or pretreated with apocynin/epalrestat, then stimulated with high uricacid, differentially expressed proteins, oxidative stress, reactive oxygen species,endothelial function were investigated after24h. Hyperuricemia was induced byinjection of oxonic acid and uric acid in aldose reductase knockout and theirwild-type mice. Oxidative stress and endothelial function were examined.Results: In this study, we compared the proteomic patterns between high uric acidand non-uric acid treated endothelial cells. It is interesting that aldose reductaseincreased significantly. Secondly, we found that under normal concentration, uric aciddefinitely reduced the three major reactive oxygen species components: superoxideanion (O2-), hydroxyl radical (·OH),1O2. But when the concentration elevated, the superoxide anion increased significantly as well as its downstream production,hydrogen peroxide (H2O2),·OH. Thirdly, in vitro, we found that increased aldosereductase expression enhanced reactive oxygen species production through activatingNADPH oxidase in endothelial cells under high uric acid. Finally, in vivo, the resultsshowed that aldose reductase knockout reduced endothelial cell impair induced byhigh uric acid, and aldose reductase inhibitor can reduce the production of hydrogenperoxide in hyperuricemic mice, and protect the function of mouse endothelial cellseffectively.Conclusion: Overproduced uric acid sequentially activates aldose reductase andNADPH, and then generates O2-,·OH and H2O2. H2O2might be the final executor ofendothelial injury. Blocking the aldose reductase pathway or degrading H2O2to water,can protect the endothelial function and keep the antioxidative feature of uric acid. Itis implied that hyperuricemia might be protective in some conditions, butoverproduced H2O2causes another injury.