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目的研究非选择性内皮素受体拮抗剂(波生坦)及血管紧张素Ⅱ1型受体拮抗剂(缬沙坦)能否抑制慢性马兜铃酸肾病(CAAN)大鼠模型肾间质纤维化的进程。方法雄性SD大鼠予关木通浸膏水溶液灌胃致成CAAN模型,并分为模型组,波生坦组(100mg·kg-1·d-1灌胃)和缬沙坦组(30mg·kg-1·d-1灌胃)。对照组予自来水灌胃。每组动物6只。检测大鼠体重、24h尿蛋白定量、β2微球蛋白(β2mG)、血清肌酐(SCr);于第16周处死大鼠,取肾组织切片做Masson染色;用RTPCR及免疫组化方法检测肾组织中转化生长因子β1(TGFβ1)、结缔组织生长因子(CTGF)、纤溶酶原激活物抑制物1(PAI1)、金属蛋白酶组织抑制物1(TIMP1)和Ⅰ型胶原(ColⅠ)mRNA及蛋白质的表达。结果与对照组相比,CAAN模型组大鼠24h尿蛋白定量、尿β2mG、SCr到实验后期均显著上升(P<0.05或0.01);肾间质纤维化面积显著性扩大(P<0.01);肾组织内TGFβ1、CTGF、PAI1、TIMP1及ColⅠ各指标的mRNA及蛋白质表达均显著上调(P<0.01)。在波生坦及缬沙坦干预组上述上调指标均被显著抑制(P<0.05或0.01),而两干预组间无明显差异(P>0.05)。结论波生坦及缬沙坦能抑制CAAN大鼠肾间质纤维化进程,延缓肾损害进展,此作用可能是通过抑制促细胞外基质合成因子(TGFβ1、CTGF)及抑制抗细胞外基质降解因子(PAI1、TIMP1)而获得。
Objective To investigate whether non-selective endothelin receptor antagonist (bosentan) and angiotensin Ⅱ type 1 receptor antagonist (valsartan) can inhibit renal interstitial fibrosis in rat model of chronic aristolochic acid nephropathy (CAAN) The process of change. Methods Male SD rats were injected with aqueous solution of Guanmutong extract into CAAN model and divided into model group, Bosentan group (100mg · kg-1 · d-1 gavage) and valsartan group (30mg · kg- 1 · d-1 gavage). The control group was fed with tap water. 6 animals per group The rats were sacrificed on the 16th week, and the kidney sections were taken for Masson staining. The renal tissues were detected by RTPCR and immunohistochemistry The expressions of transforming growth factor β1 (TGFβ1), connective tissue growth factor (CTGF), plasminogen activator inhibitor 1 (PAI1), tissue inhibitor of metalloproteinase 1 (TIMP1) and collagen Ⅰ expression. Results Compared with the control group, the 24 - hour urinary protein, urinary β2mG and SCr increased significantly (P <0.05 or 0.01) and the area of renal interstitial fibrosis significantly increased in CAAN model group (P <0.01). The mRNA and protein expressions of TGFβ1, CTGF, PAI1, TIMP1 and ColⅠ in renal tissues were significantly increased (P <0.01). In the bosentan and valsartan intervention groups, the up-regulation index was significantly inhibited (P <0.05 or 0.01), but no significant difference between the two intervention groups (P> 0.05). Conclusion Bosentan and valsartan can inhibit the process of renal interstitial fibrosis and delay the progression of renal damage in CAAN rats. This effect may be mediated through inhibition of extracellular matrix synthesis factor (TGFβ1, CTGF) and inhibition of anti-extracellular matrix degradation factor (PAI1, TIMP1).