The Effect Of Rosiglitazon On Diabetic Nephropathy Of Type 2 Diabetic Rats

Objective Diabetic nephropathy (DN) is indentified to be one of the most important microvascular complication of diabetes mellituse. Multiple factors are considered to be involved in the pathogenesis such as hereditary susceptibility, metabbolism disorder, hemodynamics, cytokines and growth factors. Recently, The studies have steped into a new stage from pathologic physiology to clinical intervention. Peroxisome proliferatoractivated receptor(PPAR) are members of the nuclear homone receptor family of ligand-actived transcription factor, three PPAR isoforms,desgnated PPARαPPARβPPARγhave been intentified due to the key role these receptors play in regulating glucoso homeostasis lipid metabolism,insulin sensitivity inflammation,atherosclersis antineoplastic action.Rosiglitazone belongs to antidiabtic thiazoladinediones drug. It's a new class of synthetic PPARγligand as well as insulin sensitizers. Rosiglitazone actinging as ligand can competivly bind PPARγand make it activated, then make it available for controling a series of important progression of physiology.According to foreign studyes, PPARγmight have indirect and direct effects to attenuate diabetic glomcrular lension, but the mechanism remains largely unknown. The purpose of this study was to detinmine whether Rosiglitazone has protective effects on diabetic nephropathy. It might be a logical approach to explore novel mechanism and search for a new strategy for protection against diabetic nephropathy.Methods 75 adult male SD rats were randomly devided into two groups: .normal diet group (20 rats, NG); high-sucrose-high-fat diet group (55 rats, HSFG). 10 rats of each group were sacrificed then a series of datas were evaluated such as serum glucose, fasting serum insulin, serum lipids in time of 8 week.The rest of 10 rats of NG were regard as group A.(control group). The rest of 45 HSFG were injected into abdominal cavity with a low dose of STZ (35 mg/kg) to induce hyperglycemia . There are 29 rats become diabetic rats model. Then they were randomly assigned 3 groups: group B ( diabetic group treated with intervention orally by a low dose RGZ 0.5 mg/kg/d); group C ( diabetic group treated with intervention orally by a large dose RGZ 3mg/kg/d);group D (diabetic group without intervention). From then, All of them were fed with normal diet . serum glucose was tested once month.at the time of 12 week, All rats of each group were sacrificed and then a series of datas were evaluated such as, serum glucose, fasting serum insulin, serum lipids, serum creatinine, blood urine nitrogen, microalbumin andα-MG,β-MG, the ratio of kidney weight to body weight, The glomerular morphology and mean glomerular area, score of mesangial matrix expand were assessed by optical microscope. The glomerular ultramicrostructure was investigated by electron microscope. The expression ofα-SMA, collage I and PPARγin kidney were examined by immunohistochemisty. Statistical analysis use SPSS10.0 statistic software.Results The HSFG rats injected with a low dose STZ show increase the ratio of kidney weight to body weight, blood glucose and fat in comparison with normal control group while ISI was reduced. That consistent with the feature of type 2 diabetic mellituse. At the time of 12 week, serum glucose, serum lipids, microalbumin,α-MG,β-MG, the ratio of kidney weight to body weight, mean glomerular area, score of mesangial matrix expand, the expression ofα-SMA and collagen I in kidney tissue of diabetic group were significantly increased in comparison with normal control group(P<0.05). While The expression of PPARγand ISI were reduced instead(P<0.05). The serum glucose, serum lipids ,microalbumin,α-MG,β-MG , the ratio of kidney weight to body weight, mean glomerular area, score of mesangial matrix expand, the expression ofα-SMA and collagen I in kidney tissue of the group of the large dose RGZ intervention were significantly lower than that of diabetic unintervention group(P<0.05); The expression of PPARγand ISI in the group of large dose RGZ intervention were significantly higher than that of diabetic unintervention group at the same time(P<0.05); Each index in the group of low dose RGZ intervention have no difference with the diabetic unintervention group. The levels of serum glucose , triglyceride,α-SMA and collagen I positively correlated with microalbumin, the ratio of kidney weight to body weight , mean glomerular area,α-MGandβ-MG(P<0.05), And negatively correlated with PPARγ, ISI(P<0.05). Each group has no difference in the level of serum creatinine, blood urine nitrogenConclusions (1) The onset of feature and pathology of the diabetic nephropathy of rats induced by fed with high-sucrose-high-fat diet and injected with low dose STZ were somehow similar with Type 2 diabetes mellituse. The Type 2 diabetic rats model were successed. (2) A large dose Rosiglitazone have indirect and direct effects to delay development and progression of diabetic nephropathy , possibly by not only regulating glucose homeostasis,lipid metabolism ,increasing insulin sensitivity, but also attenuating diabetic glomerlar and tublar lesions.All of protective effects were mediated by PPARγ. PPARγactivation decreased expression ofα-SMA collage I which contribute to the growth of extracellular matrix to avoid of glomerulosclerosis and tublular lesion . (3)A low dose Rosiglitazone has no clearly protective on diabetic nephropathy. (4)Many researches were limited to in vitro and animal study model.There are few researches basing on patient and clinic.They call on researchers to explore furtherly.