他达拉非肠溶缓释新剂型对输尿管梗阻引起的肾纤维化小鼠治疗作用的研究  

Efficacy of enteric-coated sustained-release tadalafil in ameliorating renal fibrosis due to ureteral obstruction in mice

作　　者：李壮 刘傲璐 李丽媚 余艾妮 刘繁 赵正刚 赵子建 穆云萍 李芳红 LI Zhuang;LIU Aolu;LI Limei;YU Aini;LIU Fan;ZHAO Zhenggang;ZHAO AllanZijian;MU Yunping;LI Fanghong(The School of Biomedical and Pharmaceutical Sciences,Guangdong University of Technology,Guangzhou 510006,China)

机构地区：[1]广东工业大学生物医药学院,广东广州510006

出　　处：《中国病理生理杂志》2024年第8期1463-1469,共7页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金青年项目(No.82100064);国家重点研发计划项目(No.2018YFA0800603);广州市基础与应用基础研究计划(No.202201010167);广东省重点领域研发计划项目(No.2019B020201015)。

摘　　要：目的:探讨他达拉非肠溶缓释新剂型对单侧输尿管梗阻(unilateral ureteral obstruction,UUO)引起的肾脏纤维化模型小鼠的治疗作用。方法:C57BL/6J雄性小鼠(8周龄)随机分为假手术(sham)组、UUO模型组、他达拉非新剂型治疗(1 mg/kg)组和他达拉非原研药治疗(5 mg/kg)组,每组6只。采用手术构建UUO模型,造模后连续7 d灌胃治疗。应用全自动生化分析仪检测各组小鼠血清中肌酐(serum creatinine,SCr)水平,通过肾脏组织病理学染色和Western blot实验观察他达拉非肠溶缓释新剂型对肾脏纤维化小鼠的治疗作用。结果:与sham组相比,肾脏纤维化小鼠SCr水平显著升高,肾小管可见空泡变性、扩张,伴明显炎症细胞浸润和胶原纤维沉积,纤维连接蛋白(fibronectin,FN)及α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)表达显著增加(P<0.05);他达拉非新剂型和原研药治疗均可显著降低肾纤维化小鼠SCr水平,改善患侧肾组织结构的损伤,减少胶原纤维的沉积,抑制FN及α-SMA的表达和分布(P<0.05)。结论:他达拉非肠溶缓释新剂型可显著减少肾组织间质中细胞外基质的沉积,减轻输尿管梗阻引起的纤维化和肾功能损伤,且与他达拉非原研药相比,具有低剂量、高疗效的显著优势。AIM:To investigate the therapeutic effect of enteric-coated sustained-release new dosage form of tadalafil on mice with renal fibrosis caused by unilateral ureteral obstruction(UUO).METHODS:Eight-week-old male C57BL/6J mice were divided into four groups randomly:sham group,UUO group,UUO+new dosage form of tadalafil(1 mg/kg)group and UUO+original patented drug of tadalafil(5 mg/kg)group.Surgery was performed to create a mouse UUO model,and therapeutic drugs were administered intragastrically for 7 d after modeling.A fully automated biochemical analyzer was used to detect serum creatinine(SCr)levels of each group.Through renal histopathological staining(HE staining,Masson trichrome staining,and immunohistochemistry staining)and Western blot,we assessed the therapeutic effect of enteric-coated sustained-release new dosage forms of tadalafil on kidney fibrosis in mice,as well as its effect on the expression and distribution of fibronectin(FN)and α-smooth muscle actin(α-SMA).RESULTS:Compared with sham group,the SCr levels were significantly increased in mice with renal fibrosis,and renal tubules were dilated and infiltrated with inflammation.Moreover,the expressions of FN and α-SMA were increased significantly(P<0.05).New dosage form and the original patented drug tadalafil both significantly reduced SCr levels in mice with renal fibrosis,improved the renal tissue structure on the affected side,reduced collagen fiber deposition,and inhibited FN andα-SMA ex pression(P<0.05).CONCLUSION:Enteric-coated sustained-release new dosage form of tadalafil reduces the deposit of extracellular matrix in kidney interstitial tissue and attenuates fibrosis and renal function damage caused by ureteral obstruction.New dosage form of tadalafil has significant advantages over the original patented drug because the low dose and high effectiveness.

关 键 词：他达拉非 肠溶缓释新剂型 肾纤维化 输尿管梗阻 胶原沉积 肾损伤 

分 类 号：R692[医药卫生—泌尿科学] R966[医药卫生—外科学] R363.2[医药卫生—临床医学]