长期腹膜透析对尿毒症大鼠腹膜结构的影响
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摘要
目的探讨尿毒症毒素对腹膜的损害,以及长期腹膜透析时,现常用含糖腹透液对尿毒症大鼠腹膜结构的改变。
方法30只雄性SD大鼠,随机分为对照组(C组,n=7),尿毒症生理盐水组(NS组,n=11),尿毒症腹透液组(PD组,n=12)。NS组和PD组大鼠通过5/6肾切除构建尿毒症模型,C组大鼠给与假手术后不予干预。四周后检测NS组和PD组大鼠血肌酐、尿素氮以明确尿毒症模型建立成功,并植入自制大鼠腹透管。植管2周后,NS组每日经导管腹腔给予0.9%生理盐水20ml,PD组每日给予4.25%百特腹透液20ml,均维持六周。此后同时处死三组大鼠,取腹膜壁层与脏层标本分别进行组织学检测,血管内皮生长因子(VEGF);转化生长因子β1 (TGF-β1)的免疫组化和RT-PCR分析。
结果因在尿毒症模型的构建及腹透过程中陆续有大鼠死亡或腹透管包裹堵塞而退出实验,最终C组、NS组和PD组分别有7只大鼠进入结果分析。C组、NS组和PD组超滤量分别为(5.27±0.61)ml、(3.59±0.68)ml和(-0.53±1.04)ml,与C组比较,NS组和PD组超滤量显著下降；PD组相对于NS组,超滤量减少(均P<0.05)。HE染色显示C组、NS组和PD组的壁层腹膜厚度分别为(10.51±1.81)μm、(23.91±2.18)μm和(38.68±5.35)μm；脏层腹膜血管数分别为(1.43±0.98)、(3.71±1.11)和(8.14±1.57)。PD组与其他两组比较,腹膜明显增厚,血管数明显增多,NS组相对于C组,腹膜厚度增加,血管数增多(均P<0.05)。免疫组化显示每高倍镜视野下VEGF和TGF-β1阳性细胞数PD组相对于C组和NS组大量增加,NS组与C组比较明显增加(均P<0.05)。RT-PCR分析显示NS组和PD组VEGF和TGF-β1 mRNA表达相比于C组显著上调,NS组显著高于C组(均P<0.05)。
结论尿毒症本身及非生物相容性腹透液均会引起腹膜血管新生及纤维化,从而导致超滤减少,最终使患者退出腹透。
Objective To investigate the damage of peritoneum upon uremic toxin,and the morphological alterations of peritoneum in uremic rats undergoing long-term peritoneal dialysis as well as the high glucose concentration dialysate.
Methods Thirty male SD rats were randomly divided into control group (n= 7), NS group (n=11), and PD group (n=12). A 5/6 nephrectomy was carried out in group NS and PD rats, while rats of group C underwent sham surgery and left untreated.4 weeks postoperatively, rats of group NS and PD were started to treat with daily transcatheter injection of 20ml 0.9% sodium chloride or 4.25% peritoneal dialysate respectively for 6 weeks. Then the experiment was terminated for all groups. Parietal and visceral peritoneum were obtained for morphological examination, The expression of vascular endothelial growth factor(VEGF) and transforming growth factor beta1(TGF-β1) was investigated by immunohistochemistry and RT-PCR.
Results As in the proceeding of the uremic model, nine rats of group NS and PD dropout due to death or obstruction of catheters, which lead to that only seven rats were left each group and were put into the analysis of result. It was revealed that the net ultrafiltration in group C, NS and PD were respectively (5.27±0.61) ml, (3.59±0.68) ml and (-0.53±1.04) ml. It was decreased in group NS and PD compared with group C, and decreased in group PD compared with group NS (P<0. 05). HE stain show the parietal thickness in group C, NS and PD were respectively (10.51±1.81)μm, (23.91±2.18)μm and (38.68±5.35)μm, the number of blood vessels in each group were (1.43±0.98), (3.71±1.11) and (8.14±1.57).They were significantly increased in group PD compared with group C and NS, and increased in NS group compared with group C (P<0.05).As the immunohistochemistry revealed,the positive cells of VEGF and TGF-β1 per high-power field were the most in group PD when compared with group C and group NS, and it was much more in group NS when compared with group C (P<0.05). The expression of VEGF and TGF-β1 mRNA were up-regulated in group PD compared with other two groups,and increased significantly in NS group compared with C group (P<0.05).
Conclusion Both uremia and non-biocompatible peritoneal dialysate fluid exposure may lead to peritoneal angiogenesis, fibrosis, ultrafiltration failure, and ultimately drop out from peritoneal dialysis.
方法30只雄性SD大鼠,随机分为对照组(C组,n=7),尿毒症生理盐水组(NS组,n=11),尿毒症腹透液组(PD组,n=12)。NS组和PD组大鼠通过5/6肾切除构建尿毒症模型,C组大鼠给与假手术后不予干预。四周后检测NS组和PD组大鼠血肌酐、尿素氮以明确尿毒症模型建立成功,并植入自制大鼠腹透管。植管2周后,NS组每日经导管腹腔给予0.9%生理盐水20ml,PD组每日给予4.25%百特腹透液20ml,均维持六周。此后同时处死三组大鼠,取腹膜壁层与脏层标本分别进行组织学检测,血管内皮生长因子(VEGF);转化生长因子β1 (TGF-β1)的免疫组化和RT-PCR分析。
结果因在尿毒症模型的构建及腹透过程中陆续有大鼠死亡或腹透管包裹堵塞而退出实验,最终C组、NS组和PD组分别有7只大鼠进入结果分析。C组、NS组和PD组超滤量分别为(5.27±0.61)ml、(3.59±0.68)ml和(-0.53±1.04)ml,与C组比较,NS组和PD组超滤量显著下降；PD组相对于NS组,超滤量减少(均P<0.05)。HE染色显示C组、NS组和PD组的壁层腹膜厚度分别为(10.51±1.81)μm、(23.91±2.18)μm和(38.68±5.35)μm；脏层腹膜血管数分别为(1.43±0.98)、(3.71±1.11)和(8.14±1.57)。PD组与其他两组比较,腹膜明显增厚,血管数明显增多,NS组相对于C组,腹膜厚度增加,血管数增多(均P<0.05)。免疫组化显示每高倍镜视野下VEGF和TGF-β1阳性细胞数PD组相对于C组和NS组大量增加,NS组与C组比较明显增加(均P<0.05)。RT-PCR分析显示NS组和PD组VEGF和TGF-β1 mRNA表达相比于C组显著上调,NS组显著高于C组(均P<0.05)。
结论尿毒症本身及非生物相容性腹透液均会引起腹膜血管新生及纤维化,从而导致超滤减少,最终使患者退出腹透。
Objective To investigate the damage of peritoneum upon uremic toxin,and the morphological alterations of peritoneum in uremic rats undergoing long-term peritoneal dialysis as well as the high glucose concentration dialysate.
Methods Thirty male SD rats were randomly divided into control group (n= 7), NS group (n=11), and PD group (n=12). A 5/6 nephrectomy was carried out in group NS and PD rats, while rats of group C underwent sham surgery and left untreated.4 weeks postoperatively, rats of group NS and PD were started to treat with daily transcatheter injection of 20ml 0.9% sodium chloride or 4.25% peritoneal dialysate respectively for 6 weeks. Then the experiment was terminated for all groups. Parietal and visceral peritoneum were obtained for morphological examination, The expression of vascular endothelial growth factor(VEGF) and transforming growth factor beta1(TGF-β1) was investigated by immunohistochemistry and RT-PCR.
Results As in the proceeding of the uremic model, nine rats of group NS and PD dropout due to death or obstruction of catheters, which lead to that only seven rats were left each group and were put into the analysis of result. It was revealed that the net ultrafiltration in group C, NS and PD were respectively (5.27±0.61) ml, (3.59±0.68) ml and (-0.53±1.04) ml. It was decreased in group NS and PD compared with group C, and decreased in group PD compared with group NS (P<0. 05). HE stain show the parietal thickness in group C, NS and PD were respectively (10.51±1.81)μm, (23.91±2.18)μm and (38.68±5.35)μm, the number of blood vessels in each group were (1.43±0.98), (3.71±1.11) and (8.14±1.57).They were significantly increased in group PD compared with group C and NS, and increased in NS group compared with group C (P<0.05).As the immunohistochemistry revealed,the positive cells of VEGF and TGF-β1 per high-power field were the most in group PD when compared with group C and group NS, and it was much more in group NS when compared with group C (P<0.05). The expression of VEGF and TGF-β1 mRNA were up-regulated in group PD compared with other two groups,and increased significantly in NS group compared with C group (P<0.05).
Conclusion Both uremia and non-biocompatible peritoneal dialysate fluid exposure may lead to peritoneal angiogenesis, fibrosis, ultrafiltration failure, and ultimately drop out from peritoneal dialysis.
引文
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[2]Moog F. The lining of the small intestine,Sci Am,1981,2455:116-125.
[3]Davila RM,Crouch EC. AmJ Pathol,1993;124:547～555.
[4]Rippe B.A three-pore model of peritoneal transport. Peritoneal Dialysis International, 1992;13(2):835.
[5]Williams JD, Craig KJ, Ruhland C, et al:The natural course of peritoneal membrane biology during peritoneal dialysis. Kidney Int.2003;64:S43-S49.
[6]Di Paolo N.The peritoneal mesothelium. An excretory organ.Perit Dial Int,1989,9:151-154.
[7]Inagi R, Miyata T, Yamamoto T, et al:Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells:role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis. FEBS Lett.1999; 463: 260-264.
[8]De Vriese AS, Tilton RG, Stephan CC, et al:Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane. J Am Soc Nephrol.2001; 12:1734-1741.
[9]FERRARA N. Role of vascular endothelial growth factor in the regulation of angiogenesis [J]. Kidney Int,1999,56:794-814.
[10]施敏,庄薇,钟爱民.尿毒症大鼠腹透模型的建立.江西医学院学报,2009,49(10)：25-26.
[11]Zareie M, De Vriese AS, Hekking LH, et al. Immunopathological changes in a uraemic rat model for peritoneal dialysis [J]. Nephrol Dial Transplant,2005 Jul20(7):1350-1361.
[12]周伟东,魏连波,张志锋,等.自制腹透管尿毒症大鼠腹膜透析模型的建立[J].第四军医大学学报,2008,29(8)：749-751.
[13]何永成,栾韶东,陈海波,等.非免疫性慢性肾功能衰竭大鼠模型的建立[J].宁夏医学杂志,2004,126(8)：564-565.
[14]周静,爱民,王朝阳,等.腺嘌呤制作慢性肾功能衰竭大鼠疾病模型.内蒙古医学院学报,2004,26(4)：248-250.
[15]Mujais S, Nolph K, Gokal R, et al.Evaluation and management of ultrafiltration problems in peritoneal dialysis. International Society for Peritoneal Dialysis Ad Hoc Committee on Ultrafiltration Management in Peritoneal Dialysis[J].Perit Dial Int,2000,20 Suppl 4:S5-21.
[16]Williams JD, Craig KJ, Topley N, et al. Peritoneal Biopsy Study Group:Morphologic changes in the peritoneal membrane of patients with renal disease[J]. J Am Soc Nephrol,2002, 13:470-479.
[17]Kakuta T, Tanaka R, Satoh Y, et al. Pyridoxamine imp roves functional, structural, and biochemical alterations of peritoneal membranes in uremic peritoneal dialysis rats[J]. Kidney Int, 2005,68(3):1326-1336.
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