Wnt抑制剂ICG-001对常染色体显性遗传多囊肾病模型的作用

目的探究ICG-001在体内外模型中对常染色体显性遗传多囊肾病(ADPKD)的影响。方法用体外囊泡实验模型,将MDCK细胞分为对照组和低、中、高剂量实验组(0.2,1.0和5.0μmol·L^-1),跟踪定位囊泡,拍照、测量囊泡直径,并计算囊泡生成率。根据实验结果,进一步用胚胎肾囊泡模型,确定药物对于胚胎肾囊泡的作用。用Ksp-Cre;Pkd1fl/fl(Pkd1在肾组织特异性敲除)多囊肾小鼠模型,将小鼠随机分为模型组、对照组和实验组(5 mg·kg^-1 ICG-001)。通过比较小鼠的肾重指数和组织学结果,观察药物对于体内多囊肾的治疗效果。结果体外囊泡模型实验结果显示,ICG-001可以抑制由佛司可林刺激增长的MDCK细胞囊泡,且呈剂量相关性;胚胎肾囊泡模型显示,实验组中ICG-001处理的胚胎肾与对照组相比,明显存在凋亡现象;在多囊肾小鼠模型中,实验组小鼠的肾重指数(双侧肾与体重的百分比)及苏木精-伊红染色结果与模型组小鼠相比,差异均无统计学意义。结论ICG-001在体外囊泡模型中能够抑制囊泡的发生和发展,但ICG-001会抑制胚胎肾的发育,并且无法治疗已发病小鼠的肾囊肿,因而无法作为治疗ADPKD的药物。

Effect of Wnt inhibitor ICG-001 on autosomal dominant polycystic kidney disease model

Objective To explore the effect of ICG-001 on autosomal dominant polycystic kidney disease(ADPKD)in vitro and in vivo.Methods In vitro cyst models were used.MDCK cells were divided into the control group and experimental-L,-M,-H groups(0.2,1.0 and 5.0μmol·L^-1 ICG-001).We tracked the cysts,took photos,measured the diameter of cysts and calculated the rate of cysts formation in the MDCK cyst model.According to the results,the embryonic kidney cyst model was further applied to determine the effects of ICG-001.Then,the Ksp-Cre;Pkd1fl/fl(Pkd1 specific knockout in renal tissue)polycystic kidney mouse model was used and the mice were divided into control group,model group and experimental group(5 mg·kg^-1 ICG-001).The therapeutic effect of drugs on polycystic kidney in vivo was observed by comparing the kidney weight index and histological results of mice.Results In vitro MDCK cyst experiments showed that ICG-001 had a significant inhibitory effect on the growth of MDCK cysts stimulated by forskolin in a dose-dependent manner.In the embryonic kidney cyst model,the embryonic kidneys in the experimental group showed significant apoptotic phenomena compared with the control group.Besides,there were no significant differences in renal weight index and hematoxylin-eosin staining results between the experimental group and model group.Conclusion ICG-001 can inhibit the growth of cysts in vitro,but ICG-001 interferes with the development of embryonic kidney and can not treat developed cysts in mice,so it can not be used as a drug for the treatment of ADPKD.