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目的观察血管紧张素Ⅱ(AngⅡ)及其受体在慢性环孢素A(CsA)肾毒性中的表达。方法 Sprague-Daw-ley大鼠皮下注射CsA(15mg·kg-1.d-1)4周,建立慢性CsA肾毒性模型;正常对照组皮下注射橄榄油。检测各组大鼠的体重、收缩期血压、血CsA浓度、血清肌酐、肌酐清除率;三色染色观察肾小管间质纤维化;免疫组织化学染色和蛋白质免疫印迹法分别检测AngⅡ及其受体AT1和AT2的表达。结果慢性CsA肾毒性组表现为体重减少、血肌酐上升、肌酐清除率下降、肾小管间质带状纤维化(P<0.01)。与对照组相比,毒性组大鼠AngⅡ的免疫活性明显增加(47±7vs13±4,P<0.01),主要分布于入球动脉的肾小球旁器,与肾小管间质纤维化程度紧密相关(r=0.769,P<0.001)。免疫印迹显示毒性组AngⅡ受体AT1的表达明显减少[(114±14)%vs(42±6)%,P<0.01],而AT2的表达增加[(129±23)%vs(469±43)%,P<0.01]。结论在慢性CsA肾毒性中,肾内肾素血管紧张素被激活,表现为AngⅡ免疫活性增加,这种AngⅡ免疫活性与肾小管间质纤维化紧密相关。
Objective To observe the expression of angiotensin Ⅱ (Ang Ⅱ) and its receptor in chronic cyclosporine A (CsA) nephrotoxicity. Methods CsA (15mg · kg-1.d-1) was subcutaneously injected into Sprague-Dawley rats for 4 weeks to establish a chronic CsA nephrotoxicity model. The normal control group was subcutaneously injected with olive oil. The body weight, systolic blood pressure, blood CsA concentration, serum creatinine and creatinine clearance rate were detected in each group. Tubulointerstitial fibrosis was observed by trichrome staining. Immunohistochemical staining and Western blotting were used to detect Ang Ⅱ and its receptor AT1 and AT2 expression. Results The chronic CsA nephrotoxicity group showed weight loss, elevated serum creatinine, decreased creatinine clearance and tubulointerstitial fibrosis (P <0.01). Compared with the control group, the immunological activity of AngⅡ in the toxic group was significantly increased (47 ± 7 vs13 ± 4, P <0.01), mainly distributed in the glomerular plexus of the afferent artery and closely related to the degree of tubulointerstitial fibrosis (R = 0.769, P <0.001). Immunoblotting showed that the expression of AT1 was significantly decreased in the toxic group [(114 ± 14)% vs (42 ± 6)%, P <0.01], while the expression of AT2 increased [(129 ± 23) vs 469 ± 43 )%, P <0.01]. Conclusion In chronic CsA nephrotoxicity, renal renin-angiotensin is activated, showing an increase of AngⅡ immunoreactivity, which is closely related to tubulointerstitial fibrosis.