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Protective Effect of Mycophenolate Mofetil on Renal Tubulo-interstitium and Its Mechanism in Diabetic Rats

Author: ZhangZuo
Tutor: WuYongGui
School: Anhui Medical University,
Course: Internal Medicine
Keywords: diabetic nephropathy mycophenolate mofetil tubulointerstitium osteopontin α-smooth muscle actin
CLC: R587.2
Type: Master's thesis
Year: 2008
Downloads: 69
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Abstract


Background and objective:Diabetic nephropathy(DN) is one of the most leading cause of end-stage renal disease in developing countries.Current researches in DN have focused on the pathological changes within glomerulus,and in particular the mesangium.Indeed,as with other primary glomerular diseases,the extent of tubulointerstitial injury in the diabetic kidney correlates closely with long-term renal function and is an important predictor of renal impairment.In DN,the early injury of renal tubulointerstitium is characterized by the hypertrophy of renal tubular epithelial cell,the thickening of basement membrane and the proliferation of extracellular matrix (ECM).If without effective control,it will gradually progress to renal tubule atrophy and interstitium fibrosis.Diabetic nephropathy is generally considered a nonimmune disease,But recent studies have indicated that inflammation,and more specifically pro-inflammatory cytokines,play a determinant role in the progress of DN and also in the tubulointerstitium injury.Various inflammatory cells and cytokines participated in the progression of tubulointerstitium injury.These studies in the relationship between inflammation and the tubulointerdtitial injury shows that immunodepressive drug could attenuate the progression of tubulointerstitial injury in diabetic rats.Mycophenolate mofetil a immunodepressive drug used to prevent allograft rejection,now was used in many glomerulonephritis.And there were some new detection about the drug used in some kidney disease which was not coused by immunologic etiological factors.This research will investigate protective effect of mycophenolate mofetil(MMF) on renal tubulointerstitium and its mechanism in diabetic rats.Method:Diabetes was induced by injection of streptozotocin.The diabetic state was confirmed by measurement of tail blood glucose(BG) levels using automatic biochemical analyzer.Rats were randomly separated into three groups:control(C group),diabetes(DM group) and diabetes treated with MMF(10 mg/kg/d by gastric gavage,DM+MMF group).Albumin excretion rate (AER) was determined at 8W.Tubulointerstitial morphological analysis were performed in PAS stained section.Tubulointerstitial area in the cortex was evaluated and graded as: 0,normal;1,the area of interstitial inflammation and fibosis,tubular atrophy and dilation with cast formation involving<25%of the field;2,lesion area between 25% and 50%of the field;and 3,lesions involving>50%of the field.The indices for tubulointerstital injury(TII) were calculated by averaging the grades assigned to all tubule fields.Expression of osteopontin(OPN) andα-smooth muscle actin(α-SMA) in renal tubulointerstitium were determined by immunohistochemistry method,and expression of TGFβ1 was measured by Western blot analysis.Results:1.General parameters:Rats in DM group had reduced body weight gain and increased blood glucose level.No effects on body weight and blood glucose were observed with group which treated by MMF.Kidney enlargement was observed in DM group,which was significantly reduced by treatment with MMF.In DM group,AER was significantly increased when compared to C group,treatment with MMF attenuated the increase in AER in the diabetic rats,but this level was still higher than that observed in control rats. 2.Renal histology.Comparing with control group,the DM group was characted with tubular atrophy,interstitial fibrosis,and inflammatory cell infiltration,the TII of DM group was obviously hither than the control group(0.84±0.25 vs 0.38±0.14,p<0.01),it was lessened in group treated with MMF,contrasted with DM group the TII was more lower in group which treated with MMF(0.64±0.22 vs 0.84±0.25,p<0.05)。3.Renal OPN andα-SMA expression:OPN protein immunostaining was almost not observed in tubulointerstitium in C group,andα-SMA was found only expressed in vascular smooth muscle cells.Immunostaining for OPN andα-SMA was increased significantly in DM group in tubulointerstitium.OPN mainly expressed in renal tubular epithelial cells.α-SMA immunostaining was mostly observed not only in renal tubular epithelial cells but also in tubulointersitium.The increasing expression ofα-SMA in DN was also seldomly found in the glomeruli and periphgromeruli.To compare with group DM,the overexpression was reduced by treatment with MMF.The expression of OPN andα-SMA protein in renal tubulointerstitium were significantly increased in diabetic rats (p<0.01),which were significantly inhibited by MMF treatment(p<0.01).4.Renal TGFβ1 expression:Western blot analysis noted that an increase in the amount of immunoreactive peptide was seen in kidney for DM group rats compared to that from C group rats.Densitometric analysis of the Western blot showed a 1.92 fold increase in the amount of TGFβ1 from DM group rats with respect to C group rats(p<0.01),treatment with MMF could reduced TGFβ1 protein expression by approximately 45%(p<0.05), respectively.Conclusion Our study showed that MMF can prevent renal tubulointerstitium injury in diabetic rats,which mechanism may be at least partly correlated with suppression on increased expression of OPN andα-SMA.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetic coma and other complications
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