【摘要】 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。更多还原

【Abstract】 Objective To investigate the therapeutic effects of endothelin receptor antogonist (bosentan) and angiotensinⅡtype 1 receptor antagonist (valsartan) on renal interstitial fibrosis of rats with chronic aristolochic acid nephropathy (CAAN). Methods A rat model of CAAN was established by gavage with extract of Aristolochia manshuriensis Kom intermittently, and then they were divided into the following three groups, i.e. model group, bosentan group (100 mg·kg -1·d -1 by gavage) and valsartan group ( 30 mg·kg -1·d -1 by gavage). Control group (CTR) only received tap water by gavage. Each group consisted of 6 rats. At the end of 1st, 4 th, 8 th, 12 th and 16 th week, urinary protein excretion, urinary β2 microglobumin (β2-mG) and serum creatinine (SCr) were measured. Afterwards the rats were sacrificed. The relative area of renal interstitial fibrosis on pathological section was semi-quantitatively determined. The mRNA and the protein expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen I (ColⅠ) in kidney tissue was semi-quantitatively determined with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. Results Compared with CTR, urinary protein excretion, urinary β2-mG and Scr were significantly increased (P<0.05 or 0.01) and relative area of interstitial fibrosis was also significantly enlarged in the model group (3.964±0.739%,CTR 0.158±0.059%,P<0.01). Compared with CTR, the expression of TGF-β1, CTGF, PAI-1, TIMP-1 and ColⅠmRNA and protein was significantly up-regulated in the model group (P<0.01). After intervention with bosentan or valsartan the up-regulating abovementioned parameters were all significantly inhibited (P<0.05 or 0.01). However, there was no difference between bosentan group and valsartan group. ConclusionBosentan and valsartan both can ameliorate renal interstitial fibrosis and improve renal function in rats with CAAN. These responses may result from the inhibition effects on the promoting factors of ECM synthesis (TGF-β1, CTGF)and the antagonistic factors of ECM degradation(PAI-1,TIMP-1).更多还原