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[目的]探讨普伐他汀和洛沙坦联合应用对慢性环孢素A(CsA)肾毒性模型大鼠抗纤维化作用的分子机制.[方法]取Sprague-Dawley雄性大鼠随机分为对照组(橄榄油1mg/kg)、CsA毒性组(皮下注射CsA 15mg/kg)、洛沙坦治疗组(洛沙坦10mg/kg+CsA)、普伐他汀治疗组(普伐他汀20mg/kg+CsA)、联合治疗组(CsA+洛沙坦+普伐他汀),均每日给药1次,持续4周.检测各组大鼠肾功能、收缩期血压、血脂水平;利用三色染色观察肾组织纤维化程度;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毒性组比较,普伐他汀和洛沙坦单独治疗组肾小管间质纤维化明显减轻(洛沙坦24.1%±4.0%,普伐他汀30.3%±5.2%,P<0.01,2.0%±3.0%),同时TGF-β1(洛沙坦230%±20%,普伐他汀240%±15%,P<0.01)和βig-h3(洛沙坦178%±21%,普伐他汀167%±10%,P<0.01)表达均明显降低,联合治疗进一步降低上述指标水平(肾小管间质纤维化程度13.5%±2.5%,TGF-β1 150%±28%,βig-h3 126%±9%,P<0.01).直线相关分析结果显示,βig-h3表达与TGF-β1(r=0.787,P<0.001)和肾小管间质纤维化程度(r=0.688,P<0.001)呈正相关.但是各组收缩期血压和血脂水平间差异均无统计学意义(P>0.05).[结论]在慢性CsA肾毒性中,普伐他汀和洛沙坦联合应用通过抑制βig-h3表达起到抗纤维化协同作用,而不依赖于降低血压或降低血脂作用.
[Objective] To explore the molecular mechanism of anti-fibrosis effect of pravastatin combined with losartan on chronic nephrotoxic CsA rat model. [Methods] Male Sprague-Dawley rats were randomly divided into control group (1mg / kg olive oil), CsA toxicity group (subcutaneous CsA 15mg / kg), losartan treatment group (losartan 10mg / kg + CsA) and pravastatin treatment group ), Combined treatment group (CsA + losartan + pravastatin), were administered once a day for 4 weeks.The renal function, systolic blood pressure, blood lipid levels were measured in each group; The degree of fibrosis was detected by immunohistochemistry. The expression of transforming growth factor-β1 (TGF-β1) and TGF-β-induced gene h3 (βig-h3) were detected by Northern blot, RNA in situ hybridization and Western blotting respectively. [Results] Compared with CsA toxicity group , Tubulointerstitial fibrosis was significantly reduced in the pravastatin and losartan monotherapy groups (losartan 24.1% ± 4.0%, pravastatin 30.3% ± 5.2%, P <0.01, 2.0% ± 3.0%), at the same time TGF-β1 (losartan 230% ± 20%, pravastatin 240% ± 15%, p <0.01) and βig-h3 (losartan 178% ± 21%, pravastatin 167% ± 10%, P <0.01) were significantly lower expression, combined treatment further Low level of these indicators (tubulointerstitial fibrosis 13.5% ± 2.5%, TGF-β1 150% ± 28%, βig-h3 126% ± 9%, P <0.01) .The results of linear correlation analysis showed that βig-h3 There was a positive correlation between the expression of TGF-β1 (r = 0.787, P <0.001) and the degree of tubulointerstitial fibrosis (r = 0.688, P <0.001), but there was no significant difference in the systolic blood pressure and serum lipids (P0.05). [Conclusion] In chronic CsA nephrotoxicity, pravastatin and losartan combined exert anti-fibrosis synergistic effect by inhibiting the expression of βig-h3, but not depend on lowering blood pressure or lowering blood lipid.