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

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

作者地址："[Li, Xiao-wei; Zhou, Hong; He, Jin-zhao; Qiu, Zhi-wei; Wang, Shu-yuan; Zhu, Shuai; An, Yong-pan; Ma, Ang; Li, Min; Quan, Ya-zhu; Li, Nan-nan; Ren, Chao-qun; Yang, Bao-xue] Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China; [Ran, Jian-hua; Wu, Meng-na] Chongqing Med Univ, Coll Basic Med, Dept Anat, Chongqing 400016, Peoples R China; [Yang, Bao-xue] Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing 100191, Peoples R China"

通信作者："Yang, BX (通讯作者)，Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China.; Yang, BX (通讯作者)，Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing 100191, Peoples R China."

来源：ACTA PHARMACOLOGICA SINICA

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000832861200001

JCR分区：Q1

影响因子：8.2

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：ADPKD; primary cilia; Cysts; 1-Indanone; anterograde transport motor protein

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/beta-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."

基金机构："National Natural Science Foundation of China [81974083, 81873597, 81800388]"

基金资助正文："We thank Dr. Peter Igarashi (University of Minnesota) and Dr. Stefan Somlo (Yale School of Medicine) for providing us with the Ksp-Cre and Pkd1<SUP>flox/flox</SUP> mice. This work was supported by the National Natural Science Foundation of China grants (81974083, 81873597 and 81800388)."