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

Xiao-wei Li1, Jian-hua Ran2, Hong Zhou1, Jin-zhao He1, Zhi-wei Qiu1, Shu-yuan Wang1, Meng-na Wu2, Shuai Zhu1, Yong-pan An1, Ang Ma1, Min Li1, Ya-zhu Quan1, Nan-nan Li1, Chao-qun Ren1, Bao-xue Yang1,3
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
Correspondence to: Bao-xue Yang:,
DOI: 10.1038/s41401-022-00937-z
Received: 24 January 2022
Accepted: 3 June 2022
Advance online: 29 July 2022


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.
Keywords: ADPKD; primary cilia; Cysts; 1-Indanone; anterograde transport motor protein

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