| ObjectiveTo investigate renal protective effect of Leflunomide(LEF) on early renal lesions in experimental diabetic rats and its mechanism,we observed the effects of LEF on the expression of monocyte chemoattractant protein-1(MCP-1) and nuclear factor-kappa B(NF-κB), and inflammatory cell infiltration in the kidney of diabetic SD rats models treated with Streptozotocin(STZ) .Our final aim is to elucidate the role of LEF in treatment of human diabetic nephropathy .Methods32 ones of 44 healthy cotemporary male SD rats ( weighing 200±20g)were chosen randomly. They were made diabetic models with a single celioinjection of STZ (65mg·kg-1·d-1 body weight) in 0.1 mmol/L citrate buffer(pH 4.2). Rats receiving an injection of citrate buffer were used as controls(group NC). 72 hours after treated,the diabetic rats with blood glucose levels≥16.7mmol/L were randomly divided into two groups: Diabetic rats made with STZ(group DM);Diabetic rats treated with 10mg·kg-1 LEF once daily by gavage(group DM+LEF). All the rats were allowed freely to access to food and water, without touching insulin or other glucose-lowering drugs during the experiment. Blood glucose (BG), blood urea nitrogen (BUN), serum creatinine (Scr), urine creatinine(Ucr), microalbuminuria(MAU) were measured;index number of kidney hypertrophy (kidey weight/body weight, KW/BW), creatinine clearance (Ccr) and urine albumin excretion rate(UAER) were calculated at 4th week and 8th week after treated. The structure and ultrastructrue of the kidney were examined by light and electron microscopy. The protein exprssion of macrophages antigen (ED-1),NF-κB and MCP-1 in kidney tissues were determined by immunohistochemical technique. The mRNA expression of MCP-1 in kidney tissues was quantitatively determined by Real-time Fluorescence Quantitative RT-PCR.ResultsThe rats in Group DM and Group DM+LEF ate and drunk much with much urine and thinness, but not in Group NC. No significant differences of the level of blood glucose were found between Group DM and Group DM+LEF. The level of blood glucose in Group DM and Group DM+LEF were always higher than that in Group NC at the end of the 4th week and 8th week after treated; Ccr, UAER and the hypertrophy index in Group DM+LEF were higher significantly than in Group NC, and lower significantly than in Group DM(P<0.01 or P<0.05). Both glomeruli volume and mesangium matrix in Group DM increased progressively throughout the experiment period,but that in Group DM+LEF decreased significantly in comparison with Group DM . Renal GBM observed by transmission electron microscope in Group DM+LEF was thinner than in Group DM, but thicker than in Group NC. The level of expression of NF-κB, MCP-1 and ED-1 in kidney in Group DM+LEF were much lower than in Group DM, but higher than in Group NC (P<0.01). The level of mRNA expression of MCP-1 in Group DM+LEF were lower than in Group DM, but higher than Group NC at the end of the 4th week and 8th week (P < 0.01). The degree of renal lesion was correlated with the quantities of glomerular macrophage infiltration (r=0.889,P< 0.01).ConclusionLefunomide play an important role in protecting kidney from injuring in the diabetic rats. Its protective effect in kidney may be correlated with inhibiting overexpression of MCP-1 and macrophage infiltration in renal tissue of nephritic rats, at least in a part, by down-regulating NF-κB activation. Lefunomide may control the progression of DN by inhibiting renal inflammatory reaction .
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