Objective To explore the new mechanism of the reno-protective effect of Empagliflozin.Methods The 8 weeks old male SPF grade C57/BL6J mice were randomly divided into two groups:normal control(NC)group(n=7)and high fat(HFD)group(n=23).The mice in the NC group were fed with a routine diet,and in the HFD group were fed with 60%HFD.After feeding with HFD for 12 weeks,mice were fasted for 16 hours and injected with STZ(30mg/kg)by intraperitoneal to establish diabetes model;and mice in the NC group were injected with solvent.The mice were randomly divided into dia-betes mellitus(DM)group(n=8),DM+Linagliptin intervention(DM+Lina)group(10 mg/kg,n=7)and DM+Empagliflozin intervention(DM+Empa)group(25 mg/kg,n=8).Drug intervention for 12 weeks,then blood and urine samples were col-lected,and liver and kidney function were detected by biochemical analyzer,blood β-hydroxybutyrate(β-HB)was de-tected by ELISA and urinary biochemical indexes such as microalbuminuria(MAU),retinol-binding protein(RBP),β2-microglobulin(β 2-MG),N-acetyl-β-D-glucosaminidase(NAG)were detected by biochemical kit.Kidney tissues were collected to observe the pathological changes and the expression of related protein was detected by Western blot.Re-sults The random blood glucose,body weight,total cholesterol,low density lipoprotein level,free fatty acid and creatinine in DM+Empa group were lower than those in DM group,and blood β-HB in DM+Empa group were higher than those in NC group,DM group and DM+Lina group,with statistical significance(P<0.05).The RBP,NAG and MAU of DM+Empa group were lower than those of DM group,and the differences were statistically significant(P<0.05),while the urinary β-HB of DM+Empa group was not statistically significant compared with NC group(P>0.05).The expression of sodium-coupled monocarboxylic acid transporter 1(SMCT1)in the kidney of diabetic mice is low,and the expression level of SMCT1 can be up-regulated after the intervention of Empagliflozin.Diabetic mice had ultrastructural damage of kidney,and the pathologi-cal damage could be improved after the intervention of Empagliflozin.Conclusions One of the protective effects of Em-pagliflozin on the kidney may be through increasing the expression of SMCT1 in the kidney,which may be a new target for the treatment of diabetic kidney disease.