【作者】 李娟；

【导师】 李灿；

【作者基本信息】 延边大学 ， 内科学， 2011， 硕士

【摘要】 目的：探讨普伐他汀联合洛沙坦治疗对慢性环孢素A(CsA)肾毒性抗纤维化作用的分子机制。方法：5组Sprague-Dawley大鼠分别给予橄榄油(1mg. kg-1.d-1)、CsA(15 mgkg-1.d-1皮下注射)、CsA和洛沙坦(10 mg.kg-1.d-1饮用水中)、CsA和两种药物联合治疗。检测各组大鼠的肾功能、收缩期血压、血脂水平；肾组织纤维化以三色染色观察；利用Northern杂交、RNA原位杂交、免疫印迹法分别检测转化生长因子β1(TGF-β1)和TGF-β诱导基因h3(βig-h3)的表达。结果：与CsA肾毒性相比,普伐他汀或洛沙坦单独治疗明显减轻肾小管间质纤维化[洛沙坦：(26±10)%;普伐他汀：(31±8)%,P<0.01 Vs.(45±6)%],同时伴有TGF-β1[洛沙坦：(230±20)%;普伐他汀：(240±15)%,P<0.05]和βig-h3[洛沙坦：(178±21)%;普伐他汀：(167±10)%,P<0.05]表达下调,联合治疗进一步减轻上述指标[纤维化程度：(11±5)%;TGF-β1：(150±28)%;βig-h3：(126±9)%,P<0.05 vs.单独治疗组]。直线相关分析示,βig-h3表达与TGF-β1(r=0.787,P<0.001)或肾小管间质纤维化程度(r=0.688,P<0.001)呈正向相关。然而,各组间收缩期血压、血脂水平无显著性差异。结论：在慢性环孢A肾毒性中,洛沙坦和普伐他汀联合治疗通过抑制βig-h3表达具有抗纤维化的协同作用,而不依赖于其降压或降血脂作用。更多还原

【Abstract】 Objective:To explore the anti-fibrotic mechanism of pravastatin and losartan co-treatment in a rat model of chronic cyclosporine A (CsA) nephrotoxicity.Methods:Five subgroups of Sprague-Dawley rats were given vehicle, CsA (15mg/kg s.c), CsA and losartan (10mg/kg in drinking water), CsA and pravastatin (20mg/kg in drinking water), or a combination of CsA, losartan, and pravastatin for 4 weeks. Renal function, systolic blood pressure, and lipid profiles were measured. In addition, renal histopathology (tubulointerstitial fibrosis, TIF) and expressions of transforming growth factorβ1 (TGF-β1) and TGF-βinducible gene-h3 (βig-h3) were evaluated with Northern blot, in situ hybridization, and immunoblotting.Results:Compared with the CsA-treated rats, the pravastatin or losartan-treated rats significantly decreased TIF [losartan:(26±10)%; pravastatin:(31±8)%, P<0.01 vs. (45±6)%] in parallel with down-regulating TGF-β1 [losartan:(230±20)%; pravastatin:(240±15)%, P<0.05] andβig-h3 [losartan:(178±21)%; pravastatin:(167±10)%, P<0.05] expression, and that combined treatment with losartan and pravastatin further decreased these parameters compared with giving each drug alone [TIF:(11±5)%; TGF-(31: (150±28)%;βig-h3:(126±9)%, P<0.05]. Correlation analysis revealed thatβig-h3 expression closely associated with TGF-β1 expression (r=0.787, P<0.001) and TIF (r=0.688, P<0.001). However, there were no significant differences in systolic blood pressure or serum lipid parameters between groups.Conclusion:Combined treatment with pravastatin and losartan provided synergistic effect on fibrotic processes by inhibitingβig-h3 expression in a rat model of chronic CsA-induced nephrotoxicity, and this effect was independent of their hypotensive and hypolipidemic actions.更多还原