霉酚酸酯对糖尿病大鼠肾小管—间质损伤的保护作用及机制
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摘要
背景与目的糖尿病肾病(diabetic nephropathy,DN)在我国已成为终末期肾病(end-stage renal disease,ESRD)的重要病因,既往的研究大多都集中于DN肾小球尤其系膜细胞的研究,然而正如其他一些肾小球疾病一样,相对于糖尿病肾小球病变而言其肾小管—间质病变对DN的远期预后具有更重要的意义。肾小管间质损伤早期表现为肾小管上皮细胞肥大,基底膜增厚和细胞外基质(extracellularmatrixc,ECM)增多,如未得到有效控制既将逐渐进展至肾小管萎缩和间质纤维化,最终呈现不可逆性进展进入慢性肾衰竭。晚近研究表明炎症在糖尿病肾小管—间质损伤的发生发展中发挥了重要的作用,多种细胞因子、炎症细胞参与了DN肾小管—间质损伤的进展。这些关于炎症机制的研究为一些抗炎免疫药物用于阻断糖尿病肾小管—间质损伤的进展提供了理论依据。霉酚酸酯(mycophenolatemofetil,MMF)作为免疫抑制剂以往多被用于移植术后的抗排斥反应,现临床已被用于多种肾小球肾炎。而在一些非免疫因素致病的肾病中的应用也有新的发现。本文探讨MMF对DN肾小管—间质损伤的保护作用及其可能机制。方法应用链脲佐菌素(streptozotocin,STZ)诱导大鼠糖尿病模型,糖尿病模型的成立由大鼠尾动脉抽血检测血糖(blood glucose,BG)由全自动生化分析仪检测,随机分三组:对照组、模型组与MMF给药组。MMF采取10 mg.kg~(-1).d~(-1)灌胃给药,8wk后观察尿白蛋白排泄率(albumin excrete rate,AER),肾小管-间质病理形态学变化,过碘酸希夫染色(periodic acid-schiff,PAS)染色对肾组织作病理形态学观察所测肾小管-间质面积按以下标准评分:0:正常;1:间质炎症与纤维化、肾小管萎缩与扩张伴管型形成＜25%所测区域;2:损伤面积在25～50%所测区域;3:损伤面积＞50%所测区域。肾小管-间质损伤指数(Indices for tubulointerstitial injury,TⅡ)为以上各积分中位数。应用免疫组化方法检测肾小管—间质骨桥蛋白(osteopontin,OPN)与α-平滑肌肌动蛋白(alpha-smooth muscle actin,α-SMA)蛋白表达,Western印迹检测肾组织转化生长因子β1(transforming growth factor-β,TGFβ1)蛋白表达。结果1、各组大鼠一般指标变化模型组大鼠表现为血糖升高、体重下降、相对肾重(肾重/体重)增加,MMF给药8 wk没有防止模型组大鼠血糖升高与体重下降。模型组大鼠相对肾重与AER明显高于对照组(p＜0.01),MMF给药大鼠相对肾重与AER明显低于模型组(p＜0.05)2、各组大鼠肾小管-间质病理形态学变化模型组大鼠表现为肾小管萎缩、间质纤维化、炎症细胞浸润,统计学分析显示TⅡ明显高于对照组(0.84±0.25比0.38±0.14,p＜0.01),提示本模型大鼠已出现肾小管-间质损害;MMF给药组肾小管-间质损伤明显减轻,TⅡ明显低于模型组(0.64±0.22比0.84±0.25,p＜0.05)。3、各组大鼠肾小管-间质OPN与α-SMA免疫组化指标变化对照组肾小管-间质OPN几乎无表达,α-SMA仅表达于小管-间质血管平滑肌细胞以及极少量的表达于对照组肾小管上皮细胞和间质中。模型组肾小管-间质OPN与α-SMA与对照组相比表达明显增多(p＜0.01),OPN主要表达于肾小管上皮细胞,α-SMA主要表达于肾小管上皮细胞以及小管间质中,肾小球周亦有α-SMA表达增多。MMF给药组与模型组相比,OPN与α-SMA表达明显减少(p＜0.01)。4、各组大鼠肾组织TGFβ1表达变化Western印迹条带光密度分析显示模型组肾组织TGFβ1蛋白表达较对照组增加1.92倍p＜0.01),MMF给药8wk可使肾组织TGFβ1蛋白表达下降约45%(p＜0.05)。结论MMF对糖尿病肾小管-间质损伤有明显保护作用,其机制可能部分与抑制肾小管-间质OPN与α-SMA表达有关。
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.
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.
引文
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[1].Navarro JF,Mora C.Role of inflammation in diabetic complications.Nephrol Dial Transplant,2005,20(12):2601-4.
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