The Protective Effect Of Sitagliptin On Diabetic Kidney Damage

Objective: In recent years，the number of the patients who suffered from diabeticmellitus is increasing with the improvement of living standards and lifestyles.Glucagon-like peptide-1(GLP-1) is an incretin secreted by intestinal L cells, whichcan promote with postprandial insulin secretion and inhibit glucagon secretion.However, it is inactivated by dipeptidyl peptidase-4(DPP-4) rapidly in vivo.DPP-4inhibitor is a novel oral hypoglycemic drugs, it can inhibit the degradation of GLP-1to promote insulin secretion. Recent studies have found that it have a protective effecton cardiovascular and other organs independent of hypoglycemic effect, but itsprotective effect in diabetic renal injury is not yet clear.Methods: Male wistar rats, weighing160to180g each, were selected to establishT2DM model by a method of high-fat and high-suger diet inducing insulin resistanceand a low-doze STZ intraperitoneal injection, then interfere the diabetic rats withsitagliptin and the rats were sacrificed after28weeks. In order to examine the effectsof DPP-4on diabetic renal injury, we observed blood biochemistry, urine protein,renal pathology and autophagy and mTOR signaling pathway, inflammation,oxidative damage and changes in apoptosis.Results:(1)The diabetic nephropathy model was established successfully. We foundobvious changes in the DM group compared with the control group. The bloodglucose, blood urea nitrogen and urinary albumin/creatinine ratio were increased.The autophagy and mitochondrial autophagy related protein LC3-Ⅱwas severelydecreased, meanwhile, p62, polyubiquitin aggregates, PINK1, Bnip3and Ambra1were significantly increased in the DM group. The performance of high level ofinflammation was the activated of NF-κB signaling pathway, at the same time, TLR2,TLR4and endogenous ligand HSP70, HMGB1and its downstream related moleculesPhospho-IKKβ, Phospho-IκBα expression were increased. Oxidative damage andapoptosis in the control group were also increased because of the lipid damage product4-HNE, apoptotic index cleaved caspase-3and protein damage productscarbonyl were increased.(2) We also found that the sitaglipin could inhance theactivity of autophay and inhibite inflammation and oxidative stress. The LC3-Ⅱwasincreased and p62, polyubiquitin aggregates, Ambra1and PINK1were decreasedbecause of inhibition of mTOR signaling pathway, which could be inferred from thedecresed of Phospho-mTOR. The NF-κB signaling pathway was suppressed with alow expression of Phospho-IKKβ, Phospho-IκBα.The lipid damage product4-HNEand protein damage products carbonyl were decreased.Conclusion: The results suggest that the activity of autophagy in diabeticnephropathy rat kidney was decreased and the mechanism may be activated of mTORsignaling pathway. The increased metabolism inflammation may be activated by theNF-κB signaling pathway. Finally, sitagliptin may enhance the autophagy activity,reduce oxidative damage and metabolic inflammation, which could delay theprogression of diabetic nephropathy and we speculated that the mechanism may beactivated of the mTOR signaling pathway and inhibition of the NF-κB signalingpathway.