| Objective:Dapagliflozin,a novel sodium-glucose co-transporter 2(SGLT2)inhibitor,is a new type of hypoglycemic drug.In recent years,dapagliflozin not only has a hypoglycemic effect,but also has the effect of reducing blood uric acid(SUA).But the uricosuric mechanism is unknown.This study intends to observe the changes of fasting blood glucose and blood uric acid levels in hyperuricemia and diabetes models after intervention of dapagliflozin.And we also observed pathological changes of rat kidneys and the level of OAT3,Nrf2,Keap1 to explore the possible uricosuric mechanism of dapagliflozin and influences of dapagliflozin on Nrf2 protein and Keap1 protein.Methods:SPF SD female rats(200±20g)were selected as the study subjects.The animals were fed by general feed.After 1 week of adaptive feeding,they were randomly divided into 5 groups: normal blank group(N group),hyperuricemia group(SUA group),hyperuricemia+dapagliflozin group(SUA+DAP group),diabetes group(DM group),diabetes+dapagliflozin group(DAP group).The hyperuricemia mode was orally administered by combination of ethambutol hydrochloride(300 mg/kg/d)and adenine 100 mg/(kg/d)daliy,and diabetes mode in rats was induced by one-time peritoneal injection of Streptozotocin at dose of 50 mg/kg.After 3 weeks,the blood samples were taken from the the retroorbital venous plexusof the rats,and the blood sugar and blood uric acid were measured.Rats were sacrificed and rat kidney tissue was taken.The renal histopathology of rats was observed by HE staining.OAT3 levels in rat kidney tissue were detected by immunohistochemical.Western blot measured the expression levels of OAT3,Nrf2,Keap1.Results:1.Compared with N group,fasting blood glucose was significantly increased inDM group and DM+DAP group.Compared with SUA group,fasting blood glucose was decreased in the DM+DAP group.Compared with DM group,fasting blood glucose was decreased in DM+DAP group.And the difference was statistically significant(P<0.05).2.Compared with N group,serum uric acid in SUA group and SUA+DAP group increased significantly.Compared with SUA group,serum uric acid was decreased in SUA+DAP group.Compared with DM group,serum uric acid was decreased in DM+DAP group.And the difference was statistically significant(P<0.05).3.HE staining showed that tubule dilatation,tubule epithelium flattening,inflammatory cell exudation.uric acid crystallization in the tubule lumen were observed in SUA group.Results showed that hyperuricemia model was successful.And pathology of SUA+DAP group was significantly improved,uric acid crystallization was significantly decreased.4.Immunohischemistey showed that,compared with N group,expression of OAT3 in kidney tissues of rats was decreased in SUA group and SUA+DAP group.Compared with SUA group,expression of OAT3 in kidney tissues of rats was decreased in SUA+DAP group.Compared with DM group,expression of OAT3 in kidney tissues of rats was decreased in DM+DAP group.And difference was statistically significant(P<0.05).5.Western Blot results showed that,compared with group N,expression of OAT3 in SUA group,SUA+DAP group,DM group and DM+DAP group was significantly decreased.Compared with SUA group,expression of OAT3 in SUA+DAP group was significantly increased.Compared with DM group,expression of OAT3 was increased in DM+DAP group.Compared with N group,expression of Nrf2 and Keap1 increased in SUA group,SUA+DAP group,DM group,DM+DAP group.Compared with SUA group,expression of Nrf2 and Keap1 in SUA+DAP group decreased significantly.The difference was statistically significant(P < 0.05).Conclusion:1.dapagliflozin can reduce the level of serum uric acid and up regulate expression of OAT3.OAT3 may play a role in reducing uric acid.2.Dapagliflozin can down regulate Nrf2/Keap1 signaling pathway in hyperuricemia rats. |
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