The Research On The Mechanism Of Liraglutide To Slow Diabetic Renal Injury By Inhibiting MTOR Expression

Diabetic Nephropathy is one of the most common chronic complications of diabetes. Early symptom of DN is microalbuminuria.The pathological changes include glomerular hypertrophy, increase in extracellular matrix, glomerular sclerosis and tubulointerstitial fibrosis. And recent research has shown that mTOR(mammalian target of rapamycin) plays an important role in the occurrence of DN.GLP-1 as a new antidiabetic drugs, has been used in patients with type 2 diabetes mellitus and show to significantly reduce blood glucose of diabetic patients. However, the research of application of GLP-1 to people with pre diabetes was relatively rare. Recently,more and more researchers begin to pay attention to the role of GLP-1 in other effect, such as preventing micro-vascular and macro-vascular disease.This research subject was intended to discuss whether intervene with GLP-1 analogues, liraglutide early in impaired glucose tolerance rats can reduce the incidence of diabetes and delay renal injury. At the same time, We are discussing whether liraglutide can improve PI3K-AKT-mTOR pathway to delay the progression renal injury in type 2 diabetic rats. We believe that the research will clarify the mechanism of renal protective effects of liraglutide and aprovide a theoretical basis for the application of liraglutide in patients with pre diabetes and diabetes mellitus.[objective]1.Study the protective effects of liraglutide on renal injury of rats with impaired glucose tolerance.2. Study the protective effects of liraglutide on renal injury of rats with T2DM3. Study on the possible mechanism of liraglutide to delay diabetic renal injury.[methods]SD rats,4 weeks,feeding with high-fat diet for 8 weeks,respectively,were injected 10 mg/kg and 20 mg/kg of STZ by intraperitoneal to construct the model of impaired glucose tolerance rats and type 2 diabetic rats.After the success of the modeling, IGT rats were randomly divided into IGT control group,liraglutide treatment group and settig up normal control group;Type 2 diabetic rats were randomly divided into T2DM control group, insulin treatment group, liraglutide treatment group and setting up the normal control group. During the experimental session,test fasting blood glucose, body weight every week. After 8 weeks of fat diet feeding and the intervention of liraglutide for 5 weeks,we respectively test OGTT to evaluate islet function,blood lipids, blood urea nitrogen, serum creatinine,cystatin C and albumin/creatinine ratio.Observe kidney morphology change by HE staining and electron microscope.Observe the renal tissue fibrosis by Masson staining.Immunohistochemical detect the expression of rat kidney TGF-β1, CTGF, VEGF. Western blot detect protein expression of p-mTOR,p-p70S6k in renal tissue.RT-PCR detect mRNA expression of mTOR, CTGF, VEGF mRNA, NOX-4 in renal tissue.We analysis liraglutide whether can prevent the occurrence of diabetes and improve the renal injury of impaired glucose tolerance rats.Whether liraglutide by inhibiting mTOR express delay type 2 diabetic rats kidney injury.[Results]1. High fat diet for 8 weeks, compared with normal diet group,triglyceride,body weight and epididymis fat weight in high fat-diet group rats were significantly increased.(allP<0.01);2.Compared with IGT control group, body weight, kidney weight/body weight ratio, bilateral epididymal fat weight/body weight ratio,glucose, cholesterol, triglycerides of rats treated with liraglutide were significantly reduced, (all P<0.05);3.Compared with the insulin treatment group, body weight, kidney weight/body weight ratio, bilateral epididymal fat weight/body weight ratio,blood lipids, Cystatin C, albumin/creatinine ratio of rats treated with liraglutide were significantly reduced, (all P< 0.05);4.Glomerular hypertrophy, mesangial cell expansion of type two diabetic rats treated with Liraglutide significantly improved and the number of podocytes of type two diabetic rats treated with Liraglutide significantly increased.5.Compared with the type two diabetic control group and the type two diabetic group treated with insulin,immunohistochemistry confirmed that TGF-β1, CTGF, VEGF expression level of renal tissue of type two diabetic rats treated with liraglutide was significantly reduced.6.Compared with insulin therapy group, p-mTOR, p-p70S6k protein levels of renal tissue in type two diabetic rats treated with liraglutide was significantly reduced and CTGF, VEGF, NOX-4 mRNA expression levels were significantly reduced. (all P< 0.05)[Conclusion]Renal pathological changes of some IGT rats have emerged. Early intervention with liraglutide in IGT rats can delay the progression to type 2 diabetic rats and improve renal injury; The study found that liraglutide can significantly improve the renal injury in type two diabetic rats besides hypoglycemic and delay the progress of diabetic nephropathy. Liraglutide could be acting on the renal GLP-1 receptor, and inhibit the mTOR pathway, play its renal protective effect.