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

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

Acta pharmacologica Sinica 2023 Feb

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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. © 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Citation

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. 1-Indanone retards cyst development in ADPKD mouse model by stabilizing tubulin and down-regulating anterograde transport of cilia. Acta pharmacologica Sinica. 2023 Feb;44(2):406-420