贝那普利对UUO大鼠肾间质纤维化的影响及机制研究
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摘要
目的:通过采用单侧输尿管梗阻(UUO)复制肾间质纤维化(Renal interstitial fibrosis,RIF)大鼠模型,观察贝那普利对肾间质纤维化的影响及其血液流变学和肾组织Periostin表达的变化。方法:将36只SD大鼠随机分为假手术组、模型组和贝那普利组,每组12只。模型组和贝那普利组大鼠麻醉、固定,结扎左侧输尿管。假手术组仅游离左侧输尿管,余不做任何处理。同步干预14天后,腹主动脉取血检测血液流变学指标、Scr及BUN变化;取左肾,剖开,一部分置于4%甲醛固定液固定,另一部分冻存于-80℃冰箱。HE染色及Masson染色观察肾间质变化;免疫组化检测肾组织I型胶原蛋白(Collagen-I);ELISA方法检测各组大鼠肾组织AngII、TGF-β1、Periostin蛋白水平的变化;RT-PCR检测各组大鼠肾组织TGF-β1 mRNA和Periostin mRNA表达的变化。结果:(1)肾功能指标:与假手术组比较,模型组血清肌酐和尿素氮含量显著升高(P < 0.05),贝那普利组与模型组比较,血清肌酐和尿素氮含量显著降低(P < 0.05)。(2)HE染色观察:与假手术组比较,模型组肾小管明显扩张变宽,可见管型,肾间质大量炎症细胞浸润,纤维化明显。贝那普利组肾小管稍增宽,少量炎症细胞浸润、无明显的纤维化改变。(3)Masson染色显示假手术组大鼠肾脏胶原染色主要位于肾小球基底膜、Bowman囊、系膜区和肾小管间的毛细血管周围。模型组大鼠肾间质宽度增加,亮绿色胶原沉积显著,肾小管上皮细胞萎缩,管腔扩张,弥漫的单核、淋巴细胞浸润和成纤维细胞增生及胶原纤维化形成,纤维化程度明显。贝那普利组较模型组,肾小管扩张、间质增宽程度及胶原在间质沉积程度均显著降低。(4)血流变学的变化:和假手术组对比,模型组的血流高、中、低切变率下的全血黏度(BV)、血浆黏度(PV)、红细胞压积(Hct)等指标显著升高(P < 0.05),贝那普利组与模型组相比显著降低(P < 0.05)。(5)免疫组化检测Ⅰ型胶原结果提示:模型组术后2周肾小管间质可见明显棕黄色物质表达,与假手术组相比显著升高(P < 0.05),贝那普利组与模型组相比显著降低(P < 0.05)。(6)ELISA检测结果显示模型组大鼠肾组织Periostin蛋白、TGF-β1蛋白、AngII蛋白大量表达,与假手术组相比均显著升高,贝那普利组与模型组相比显著降低,(P < 0.05)。(7)RT-PCR结果表明, Periostin mRNA在模型组大鼠肾组织大量表达,比假手术组增多85.37%(P<0.05),贝那普利组与模型组相比显著降低(P<0.05),和假手术组相比在模型组大鼠肾组织TGF-β1mRNA显著增多(P<0.05),贝那普利组与模型组相比显著降低(P<0.05)。结论:贝那普利可延缓肾间质纤维化进程,使肾功能得到保护,其机制可能是通过改善UUO肾间质纤维化大鼠的血液流变性,抑制AngII-TGF-β1信号系统下调Periostin的表达,减少胶原蛋白的合成,从而改善肾间质纤维化。
Abstract :Objective: To study the effect and mechanisms of benazepril on renal interstitial fibrosis induced by unilateral ureteral obstruction(UUO) in rats. Methods: The 36 SD rats were randomly divided into sham operation group, Model group and Benazepril group, 12 in each group. Model group and Benazepril rats were anesthetized, fixed, ligating the left ureter. Sham operation group, only free on the left ureter, and not to be obstructed. After synchronous intervention for 14 days, Abdominal aortic blood was collected, mensurated hemorrheologic indexes and serum BUN, creatinine. Left kidney was taken, HE staining and Masson staining observed renal interstitial changes; The expression of Collagen-I in kidney tissue was detected by the immunohistochemical method; ELISA method was used to detect the expression level of Collagen-I protein, AngII protein, TGF-β1 protein in kidney tissue; RT-PCR determine the expression changes of TGF-β1mRNA and Periostin mRNA in renal tissue. Results: (1) Renal function: Compared with model group, benazepril reduce the serum concentration of SCr and BUN of unilateral obstruction in rats significantly (P < 0.05). (2) HE staining: Compared with sham operation group, renal tubule was significantly expanded wider, showing interstitial inflammatory cell infiltration, significant degree of renal interstitial fibrosis in the model group rats,Compared with the model group, benazepril group inflammatory cells and the level of renal interstitial fibrosis were obviously decreased, no significant fibrosis. (3) Masson staining: the sham groups, Masson staining showed that collagen are mainly located in renal glomerular basement membrane, Bowman capsule, mesangial area and around the capillaries between renal tubulesin. Compared with the sham groups, in the Model rats, green collagen significantly increased, the width of renal interstitial broadened, tubular epithelial cell atrophy, luminal expanded, collagen fibrosis, renal interstitial fibrosis was significant. Compared with the model group, the extent of interstitial widening and degree of collagen deposition in interstitium was reduced significant- ly in benazepril group. (4) Changes in blood rheology: Compared with model group, benazepril could significantly reduce whole blood viscosity(WBV), plasma viscosity (PV),hematocrit(Hct), etc. (P < 0.05). (5) Immunohistochemistry results suggest that collagen type I: Compared with model group, collagen type I was decreased significantly in the rats of benazepril group (P < 0.05). (6) ELISA: compared with sham group, the expression of TGF-β1, Periostin, AngII, that in the interstitium of model group increased (P < 0.05), compared with model group, benazepril group were decreased significantly (P < 0.05), (7) RT-PCR: compared with the sham group, the expression of Periostin mRNA, were significantly increased about 85.37%, (P < 0.05), compared with model group, benazepril group were reduced significantly (P < 0.05),compared with the sham group, the expression of TGF-β1mRNA were increased significantly (P < 0.05), compared with model group, benazepril group were reduced significantly (P < 0.05). Conclusion: Benazepril may reduce the level of hemorheology indices to improve rat renal interstitial fibrosis and delay the process of renal interstitial fibrosis; Benazepril could reduce the expression of Periostin to improve the renal interstitial fibrosis by inhibiting Signal Transduction of AngII-TGF-β1.
Abstract :Objective: To study the effect and mechanisms of benazepril on renal interstitial fibrosis induced by unilateral ureteral obstruction(UUO) in rats. Methods: The 36 SD rats were randomly divided into sham operation group, Model group and Benazepril group, 12 in each group. Model group and Benazepril rats were anesthetized, fixed, ligating the left ureter. Sham operation group, only free on the left ureter, and not to be obstructed. After synchronous intervention for 14 days, Abdominal aortic blood was collected, mensurated hemorrheologic indexes and serum BUN, creatinine. Left kidney was taken, HE staining and Masson staining observed renal interstitial changes; The expression of Collagen-I in kidney tissue was detected by the immunohistochemical method; ELISA method was used to detect the expression level of Collagen-I protein, AngII protein, TGF-β1 protein in kidney tissue; RT-PCR determine the expression changes of TGF-β1mRNA and Periostin mRNA in renal tissue. Results: (1) Renal function: Compared with model group, benazepril reduce the serum concentration of SCr and BUN of unilateral obstruction in rats significantly (P < 0.05). (2) HE staining: Compared with sham operation group, renal tubule was significantly expanded wider, showing interstitial inflammatory cell infiltration, significant degree of renal interstitial fibrosis in the model group rats,Compared with the model group, benazepril group inflammatory cells and the level of renal interstitial fibrosis were obviously decreased, no significant fibrosis. (3) Masson staining: the sham groups, Masson staining showed that collagen are mainly located in renal glomerular basement membrane, Bowman capsule, mesangial area and around the capillaries between renal tubulesin. Compared with the sham groups, in the Model rats, green collagen significantly increased, the width of renal interstitial broadened, tubular epithelial cell atrophy, luminal expanded, collagen fibrosis, renal interstitial fibrosis was significant. Compared with the model group, the extent of interstitial widening and degree of collagen deposition in interstitium was reduced significant- ly in benazepril group. (4) Changes in blood rheology: Compared with model group, benazepril could significantly reduce whole blood viscosity(WBV), plasma viscosity (PV),hematocrit(Hct), etc. (P < 0.05). (5) Immunohistochemistry results suggest that collagen type I: Compared with model group, collagen type I was decreased significantly in the rats of benazepril group (P < 0.05). (6) ELISA: compared with sham group, the expression of TGF-β1, Periostin, AngII, that in the interstitium of model group increased (P < 0.05), compared with model group, benazepril group were decreased significantly (P < 0.05), (7) RT-PCR: compared with the sham group, the expression of Periostin mRNA, were significantly increased about 85.37%, (P < 0.05), compared with model group, benazepril group were reduced significantly (P < 0.05),compared with the sham group, the expression of TGF-β1mRNA were increased significantly (P < 0.05), compared with model group, benazepril group were reduced significantly (P < 0.05). Conclusion: Benazepril may reduce the level of hemorheology indices to improve rat renal interstitial fibrosis and delay the process of renal interstitial fibrosis; Benazepril could reduce the expression of Periostin to improve the renal interstitial fibrosis by inhibiting Signal Transduction of AngII-TGF-β1.
引文
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3. Koo JW,Kim Y,Rozen S,et a1.Enalapril accelerates remodeling of the renal interstitium after release of unilateral ureteral obstruction in rats[J]. J Nephrol, 2003, 16(2): 203-209
4.王晓莹,王继明.肾小管间质纤维化与细胞因子调控异常相关性研究[J].吉林医学. 2007, 28(17):1913. 6
5. Rupcrez M, Ruiz Ortega M, Esteban V, et a1. AngiotensinII increases CTGF in the kidney[J]. J Pathol, 2O03, 163(5):1937
6. Jensen AM, Bae EH, Fenton RA, et a1. Angiotensin II regulates V2 receptor and pAQP2 during ureteral obstruction[J]. Am J Physiol Renal Physiol, 2009, 296(1):127-134
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