The Protective Effects Of Osteoprotegerin On Diabetic Nephropathy Rats And Its Mechanism

Background:Diabetic nephropathy is one of the diabetic serious microvascular complications, It isone of the primary death cause of Diabetes mellitus(DM), Approximately20%to30%of type2diabeticswill develop evidence of nephropathy, although a higher percentage of type1patients progress toESRD,which has become the primary cause of ESRD in the worldwide, The pathogenesis of DN iscomplex, the mechanism of dysfunction has not yet been clarified.which is the result of disorders ofhemodynamic, cytokines, growth factors and other factors changes because of glucose metabolism.Diabetic nephropathy has once emerging progressive increase in proteinuria,so the glomerular filtration rate(GFR) and Renal function declines progressively in patients of DN, The pathogenesis should not bereverted.Clinically, diabetic nephropathy has a high risk of morbidity and mortality.So it is important totherapeutic interventions in earlier period of the pathogenesis of DN.Glomerular endothelial cells (GECs) are specialized cells with important roles in physiologicalfiltration and glomerular disease. The continuous hyperglycemia is first responsible for injury of vascularendothelium. Increase of urinary protein is to indicate the abnormality of renal microvascular system inDM. Being Glomerular endothelial cells(GECs) exposed to the bloodstream, it has been injuried byhyperglycemia, hypertension, and the local renin-angiotensin system,so that may induce these cells torelease inflammatory cytokines, which can promote diabetic renal hypertrophy and glomerulus sclerosisand extracellular matrix formation, thus promoting diabetic nephropathy occurrence and development. Thestructural and functional injury of Glomerular endothelial cells(GECs) were important to the progression ofDiabetic nephropathy(DN). At present, how to decrease injury of GECs,Which plays an important role inthe treatment of diabetic nephropathy.According to present research, Osteoprotegerin(OPG) has been found to promote endothelial cellsurvival and vascular maturation,OPG have could protect effect in progression of diabetic nephropathy, Butit’s mechanism is not known,So it is really worth studying.In this experiment, DN animal model thatinduced by high-fat diet and Streptozocin was first established, and carried on the intervention by usingOPG to observe24hours’ albumin, serum creatinine and pathomorphology of renal tissue, meanwhile themechanism of OPG in kidney disease was discussed. Objective:(1). The study aims to investigate the influence of OPG on renal function in diabeticnephropathy rat models.So as to estimate the effect of OPG to protect the kidney.(2). The study woulddetermine the effect of OPG on expression of CD34andMCP-1by immunohistochemistry in kidneys.So asto study its mechanism of protecting the kidney.Methods: We establish Diabetic nephropathy rat models by feeded high lipid diet and injectionedwith low-dose of STZ.Thirty DN model rats were randomly divided into two groups:DN model group(n=15),OPG group(n=15).In addition, the normal control group(n=15).The OPG group rats were injectedintraperitoneally by OPG(8ug／kg)per day for10weeks, Rats in normal control group and DN modelgroup were injected intraperitoneally by identical volum of physiological saline daily,Feed and water intakewas also noted for control in the various sample groups. At the end of the experiments,the weight of ratswere observed, after24-hour urine samples collection, which was used for detecting24hours’ albumin.and final blood samples were obtained via cardiac puncture.After rats were killed,Serum was isolatedfrom the samples after centrifuging,which was used to determine creatinine and urea nitrogen and glucoselevels in the various sample groups. The weight of kindey was observed after Cleaning the kidney. Kidneyswere cut and fixedt with10%formalin,which stained to show kidney pathological changes with Massonand PASM by light microscope.CD34and MCP-1expression in kidneys were determined byimmunohistochemistry．Results：(1). Compared to DN group, the24hours urinary albumin, blood urine nitrogen andcreatinine and the function of kidney of OPG-treated were better than DN;(2). Compared to DN group,thepathological changes by light microscope in kidney of OPG-treated group were better than DN;（3）. Thedensity of Glomerular endothelial cells (The expression of CD34)in OPG group increased compared withDN group;(4).The expression of MCP-1in OPG group decreased compared with diabetic nephropathygroup;（5）The level of24hours urinary albumin and glomerulosclerosisindex and interstitial fibrosis indexwere negatively correlated with the the density of Glomerular endothelial cells;(6). The density ofGlomerular endothelial cells was negatively correlated.The expression of MCP-1in kidneys.Conclusion：(1).OPG can decrease24hours urinary albumin and improve the kidney function ofdiabetic nephropathy rats;(2).OPG can delay the kindey pathological changes of diabetic nephropathyrats.(3).OPG can increase the density of Glomerular endothelial cells to protect the kidney and decrease the expression of MCP-1.