1-Indanone retards cyst development in ADPKD mouse model by stabilizing tubulin and down-regulating anterograde transport of cilia  

作　　者：Xiao-wei Li Jian-hua Ran Hong Zhou Jin-zhao He Zhi-wei Qiu Shu-yuan Wang Meng-na Wu Shuai Zhu Yong-pan An Ang Ma Min Li Ya-zhu Quan Nan-nan Li Chao-qun Ren Bao-xue Yang 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,Department of Pharmacology,School of Basic Medical Sciences,Peking University,Beijing 100191,China [2]Department of Anatomy,College of Basic Medicine,Chongqing Medical University,Chongqing 400016,China [3]Key Laboratory of Molecular Cardiovascular Sciences,Ministry of Education,Beijing 100191,China

出　　处：《Acta Pharmacologica Sinica》2023年第2期406-420,共15页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China grants(81974083,81873597,81800388).

摘　　要：Autosomal dominant polycystic kidney disease(ADPKD)is the most common inherited kidney disease.Cyst development in ADPKD involves abnormal epithelial cell proliferation,which is affected by the primary cilia-mediated signal transduction in the epithelial cells.Thus,primary cilium has been considered as a therapeutic target for ADPKD.Since ADPKD exhibits many pathological features similar to solid tumors,we investigated whether targeting primary cilia using anti-tumor agents could alleviate the development of ADPKD.Twenty-four natural compounds with anti-tumor activity were screened in MDCK cyst model,and 1-Indanone displayed notable inhibition on renal cyst growth without cytotoxicity.This compound also inhibited cyst development in embryonic kidney cyst model.In neonatal kidney-specific Pkd1 knockout mice,1-Indanone remarkably slowed down kidney enlargement and cyst expansion.Furthermore,we demonstrated that 1-Indanone inhibited the abnormal elongation of cystic epithelial cilia by promoting tubulin polymerization and significantly down-regulating expression of anterograde transport motor protein KIF3A and IFT88.Moreover,we found that 1-Indanone significantly down-regulated ciliary coordinated Wnt/β-catenin,Hedgehog signaling pathways.These results demonstrate that 1-Indanone inhibits cystic cell proliferation by reducing abnormally prolonged cilia length in cystic epithelial cells,suggesting that 1-Indanone may hold therapeutic potential to retard cyst development in ADPKD.

关 键 词：ADPKD primary cilia CYSTS 1-Indanone anterograde transport motor protein 

分 类 号：R69[医药卫生—泌尿科学]