The Effect Of Glucagon-like Peptide-1 Receptor Agonist Liraglutide On Renal Endoplasmic Reticulum Stress Of Type 2 Diabetic Rats

Objective:To study the protective effect and related mechanism of new glucagon-like peptide-1 receptor agonist liraglutide on renal of type 2 diabetic rats and provide new strategy for the prevention and treatment of diabetic nephropathy.Methods:After a one-week adaption by standard diet,twenty-four of thirty male SD rats were fed high-sugar and high-fat diet together with intraperitoneal injection of streptozotocin to establish type 2 diabetic models,the rest were continuously provided standard diet.After successful modeling,all rats were divided into four groups:normal control group(group N),diabetic control group(group D),high-dose liraglutide group(group H),low-dose liraglutide group(group L).Group H and L were respectively given subcutaneous injection of liraglutide at dose of 200ug/kg/d and 100ug/kg/d,whereas group N and D were given subcutaneous injection of saline.After a 8-week intervention,all rats were sacrificed to test fasting insulin(FINS),fasting blood glucose(FBG),blood urea nitrogen(BUN),serum creatinine(Scr),total cholesterol(TC),triglycerides(TG),highdensity lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),24 hour urine protein quantitation,urine microalbumin(m Alb),urine microalbumin/creatinine(MAl/C)and HOMA-IR.Using methods of RT-PCR and western blot to detect the relative expression of endoplasmic reticulum stress markers GRP78,caspase12,p-JNK in renal of each group.Results:1.General condition among four groups of ratsThe rats in group N had good mental state,quick response and shiny hair.Compared with group N,rats in group D had poor spirit,lethargy,blunt reaction,darkening hair,obvious symptoms of polydipsia,polyphagia,polyuria,frequent litter replacement.After intervention with liraglutide,the mental state,response and hair of rats in group H and L were better than that in group D,but worse than group N.2.Effect of liraglutide on serological indicators,urine indexesFBG,FINS,TC,Scr,BUN,24 hour urine protein quantitation,mAlb,MAl/C,HOMA-IR in group D were significantly increased than that in group N(P<0.05).However,there were no significant differences in TG,HDL-C,LDL-C(P>0.05).After intervention with liraglutide,FBG,FINS,Scr,BUN,24 hour urine protein quantitation,urine mAlb,MAl/C,HOMA-IR in group H and L were significantly decreased than that in group D(P<0.05),and group H was lower than group L(P<0.05).However,there were still no significant differences in TC,TG,HDL-C,LDL-C(P>0.05).3.Effect of liraglutide on relative m RNA expression of endoplasmic reticulum stress markers in renal of each groupThe m RNA expression of endoplasmic reticulum stress markers GRP78,caspase12 were detected by RT-PCR.The results showed that the level of the above markers in group D was increased than that in group N(P<0.05).After intervention with liraglutide,the mRNA level in group H and L were significantly decreased than that in group D(P<0.05),and group H was lower than group L(P<0.05).4.Effect of liraglutide on relative protein expression of endoplasmic reticulum stress markers in renal of each groupThe protein expression of endoplasmic reticulum stress markers GRP78,caspase12 and p-JNK were detected by western blot.The results showed that the level of the above markers in group D was increased than that in group N(P<0.05).After intervention with liraglutide,the protein level in group H and L were significantly decreased than that ingroup D(P<0.05),and group H was lower than group L(P<0.05).Conclusion:Liraglutide,a new kind of glucagon-like peptide-1 receptor agonist,has protective effect on renal of diabetic rats by improving fasting blood glucose,fasting insulin,serum creatinine,urea nitrogen,insulin resistence and reducing urine protein excretion.The related mechanism may involve in reduction of endoplasmic reticulum stress in renal.