The Effect Of OXM Analogues On Renal Fibrosis In Chronic Kidney Disease

Background and purpose of the study: Renal fibrosis is the most important pathological feature of various chronic kidney diseases(CKD)in the late stage.However,there are currently no drugs that can effectively treat or reverse the development of renal fibrosis.Therefore,it is of great clinical significance to find drugs and methods that can effectively cure renal fibrosis.As a peptide hormone,Oxyntomodulin(OXM)can simultaneously activate two receptors,glucagon like peptid-1 receptor(GLP1R)and glucagon receptor(GCGR).It can reduce blood glucose and body weight.Several studies have demonstrated that OXM shows better effect on weight loss and blood glucose regulation than pure GLP1 R agonists,and the activation of GCGR by OXM could avoid the risk of hypoglycemia caused by single GLP1 R agonist,which increases the safety and dependence of drug application.At present,there is no relevant report on whether OXM has a potential protective effect on the kidney.In this study,we hope to provide a new strategy for the treatment of renal fibrosis.However,endogenous OXM is easily degraded by enzymes produced in the body due to the nature of peptides.Therefore,we designed and synthesized six long-acting OXM analogues(OA1-OA6),and studied their effects on renal fibrosis and screened the dominant compound through the vitro and vivo experiments.Methods:(1)In vitro experiments: Glomerular mesangial cells(MCs)and human tubular epithelial cells(TECs)were cultured with high glucose,and the effects of OXM analogues on cell proliferation and the expression of fibrosis related factors were detected by MTT,Western Blot and ELISA experiments.(2)Streptozotocin(STZ)induced diabetic nephropathy mouse model: the diabetic mouse model was induced by intraperitoneal injection of STZ citric acid solution.The effects of OXM analogues on renal function,the degree of renal fibrosis and expression of fibrosis related factors in diabetic nephropathy mice were determined by biochemical indexes,pathological section staining,immunohistochemistry and RT-PCR.(3)Unilateral ureteral obstruction(UUO)renal interstitial fibrosis mouse model: the renal interstitialfibrosis mouse model was performed by ligation of the left ureter of mice.The effects of OXM analogues on renal function and the degree of renal fibrosis in UUO mice were determined by biochemical indexes and pathological section staining.Results:(1)The results in vitro experiments showed that OA2 could inhibit the excessive proliferation of MCs and TECs induced by high glucose stimulation,and reduce the expression of fibrosis related factors in cells.OA2 is superior to OA1 and OA3-OA6 in inhibiting renal fibrosis at the cellular level.(2)In STZ induced diabetic nephropathy mice model experiment,OA2 could improve renal function,down regulate the expression of renal fibrosis related factors,reduce the degree of renal fibrosis in diabetic nephropathy mice.OA2 is superior to the OA1,OA3-OA6 and liraglutide in inhibiting renal fibrosis.(3)In a mouse model of UUO renal interstitial fibrosis,OA2 could improve renal function and reduce the collagen deposition in kidney tissue in UUO mice,but it could not improve the renal intermal injury caused by ureteral obstruction.Conclusion: Among the six OXM analogues in the study,the analogue OA2 was screened out to effectively inhibit the high-glycose-induced proliferation of MCs and TECs,and the expression of fibrosis-related factors at the cellular level.It has the effect of improving the kidney fibrosis induced by STZ in diabetic nephropathy mice and protecting the kidney in animal experiments,which can be further studied.This study provides novel ideas for the research and application of OXM analogues,and provides new targets and strategies for the treatment of renal fibrosis.