This study aims to investigate the intervention effect of hyperoside (Hyp) on diabetic kidney disease(DKD) mice induced by combining high-fat feed with intraperitoneal injection of streptozotocin (STZ).Thirty-two eight-week-old male C57BL/6J mice,weighing (20 ± 2) g,were randomly divided into two groups:control group (n = 8) were fed basal diet and DKD group (n =24) fed with high-fat diet for six weeks.Twenty-four DKD mice were randomly selected as the model group (group M),Hyp group (group H,200 mg/kg) and simvastatin group (group S,5.2 mg/kg).After 16 weeks intragastric administration of the corresponding drugs,urine,serum,and renal tissues were collected,and the histopathological changes of the kidneys were observed by using HE,Masson,and PAS;Total cholesterol (total cholesterol,TC),triglyceride (triglyceride,TG),high-density lipoprotein cholesterol (high-density lipoprotein cholesterol,HDL-C),low-density lipoprotein cholesterol (low-density lipoprotein cholesterol,LDL-C),glucose (glucose,GLU),blood urea nitrogen (blood urea nitrogen,BUN),creatinine (serum creatinine,Scr) in serum,urea nitrogen (blood urea nitrogen,BUN) and creatinine (urine creatinine,Ucr) in urine were detected by biochemical assays;insulin (insulin,INS),cystatin C (cystatinC,CysC),acute C-reactive protein (C-reactive protein,CRP) in serum and urinary protein (urinary protein,UP),microalbumin (microalbuminuria,mALB) in urine were examed by ELISA;and the insulin resistance index (homeostatic model assessment for insulin resistance,HOMA-IR) was calculated.Compared with group N,group M showed obvious infiltration of inflammatory factors,partial glomerular desertion,and obvious fibrosis and glycogen deposition in renal tissues;TC,HDL-C,LDL-C,GLU,BUN,and CRP in serum were significantly higher (P<0.01),and the CysC in serum increased (P<0.05);UP and mALB in urine were significantly higher (P<0.01);and the HOMA-IR obviously higher (P<0.01).Compared with group M,group H reduced the infiltration of inflammatory factors,significantlydecreased renal tissue fibrosis and glycogen deposition;diminished the levels of TC,LDL-C,GLU,CysC,CRP (P<0.05) in serum,and significantly decreasedthe levels of BUN (P<0.01),UP (P<0.05),and mALB (P<0.01) in urine;and HOMA-IR decreased (P<0.05).In conclusion,Hyp can intervene C57BL/6J mice DKD induced by high-fat feed combined with intraperitoneal injection of STZ,possibly achieved by regulating glucose and lipid metabolism,inhibiting inflammatory responses,reducing early kidney injury,improving glomerular filtration function,and reducing renal tissue fibrosis.