Effect Of DPP-Ⅳ Inhibitor Sitagliptin On ERK1/2 Signal Pathway In Diabetic Nephropathy Rats

Objective:Observe sitagliptin on diabetic nephropathy(DN) rats renal protective effects and impact on ERK1/2 signaling pathways.Methords:Choose 40 clean and healthy male Wistar rats were divided into normal control group(NC)diabetes nephropathy group(DN),sitagliptin small dose of statins intervention group(ST1), sitagliptin high-dose statins intervention group(ST2), by random number method,10 in each group.With high sugar,high fat feed and intraperitoneal injection of STZ DN rat model was established.After building,the ST1 group and ST2 group were given different doses of the drug lavage treatment(5mg ?kg-1 ?d-1、10mg ?kg-1 ?d-1);Respectively at 0w,4w,8w,12 w,16w to observe each rat body weight, detection of blood glucose(BG),the change of the Urinary albumin excretion rate(AER),At the and of 16 weekend,glycated hemoglobin(Hb A1C),serum creatinine(Scr) were detected and record kidney weight and body weight.HE,PAS and PASM staining was performed on renal tissue to observe left kidney kidney tissues pathology;the expression of podocalyxin,bax/bcl-2,ERK1/2,DPP-IV and GLP-1 in renal interstitium were detected by immunohistochemitry;and the expression level of podocalyxin,bax/bcl-2,ERK1/2,DPP-IV and GLP-1 were detected via real-time PCR.Results:1.Compared with NC group,the DN group,the weight of ST1 group and ST2 group ratssignificantly reduce(P<0.05),but the differences of DN group,ST1 group and ST2 group showed no statistically significant(P>0.05).2. At the end of 16 th week,The ST1 group, ST2 group and DN group(BG) [(15.7±0.5),(11.0±0.4) than(21.52±0.2) mmol/L],urinary albumin excretion rate(AER) [(78.21±0.02),(65.45±0.96) than(90.67±0.57)mg/d],Scr[(93.34±9.42),(80.23±7.02)than(110±8.2)umol/L],Hb A1C[(8.1±0.02),(7.5±0.01)than(9.0±0.12)] and kidney hypertrophy index [(9.10±0.65),(7.24±0.34) than(12.34±0.23)],compared each numerical below DN group(P<0.05),then the ST2 group changes was more obviously(P<0.05).The difference was statistically significant.3.Kidney tissues light microscope results:NC group rat glomerular, renal tubule and renal interstitial area structure is clear, no obvious pathological changes.DN group of glomerular volume increase,part of glomerular capillary tube cavity expansion,mesangial matrix was increased,mesangial cells increased obviously,diffuse thickening of basement membrane, renal tubular vacuoles degeneration,capillary and visible focal lymphocytic interstitial mononuclear cell infiltrates.Compared with the DN group,the ST1 group and ST2 group rat glomerular mesangial matrix proliferation,inflammatory cells infiltration reduction,then ST2 is improved more obviously.4.Immunohistochemical result: compared with DN, sitagliptin intervention group(ST1,ST2) glomerular podocyte podocalyxin marker protein,the expression of GLP-1 protein expression significantly increased(P<0.05);DPP-IV,bax/bcl-2,ERK1/2 protein significantly decreased(P<0.05), compared with the ST1 group,the ST2 group changes more apparent(P<0.05),the difference was statistically significant.5.Real-time fluorescent quantitative PCR results: compared with DN group, ST1 group and the ST2 group glomerular podocyte podocalyxin marker protein, the expression of GLP-1 m RNA increased significantly(P<0.05);DPP-IV,bax/bcl-2 and ERK1/2 m RNA were significantly lower(P<0.05), the ST2 group changes was more obviously(P<0.05).The difference was statistically significant.Conclusion:1.Sitagliptin can lower BG,AER levels of DN rats,reduce pathological damage on glomerular,delay the early DN progress,have a protective effect to the kidney.2.Sitagliptin improve proteinuria and delay DN progress,its mechanism may be inhibition of ERK1/2 to activate signaling pathways,bax/bcl-2 significantly decreased, thus inhibiting apoptosis of glomerular podocyte.This may be one of the renal protective mechanism of outside independent of hypoglycemic.