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

• Published in: Acta pharmacologica Sinica Vol. 44; no. 2; pp. 406 - 420
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.02.2023; Nature Publishing Group
• Subjects: Animals; Anterograde transport; Antitumor agents; Biomedical and Life Sciences; Biomedicine; Cell growth; Cell proliferation; Cilia; Cysts; Cysts - metabolism; Cysts - pathology; Cytotoxicity; Embryogenesis; Epithelial cells; Epithelial Cells - metabolism; Hedgehog protein; Hedgehog Proteins - metabolism; Immunology; Internal Medicine; Kidney - pathology; Kidney diseases; Medical Microbiology; Mice; Mice, Knockout; Neonates; Pharmacology/Toxicology; Polycystic kidney; Polycystic Kidney, Autosomal Dominant - drug therapy; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Protein transport; Signal transduction; Solid tumors; Therapeutic targets; TRPP Cation Channels - metabolism; Tubulin; Tubulin - metabolism; Vaccine; Wnt protein; β-Catenin; ADPKD; Cysts; anterograde transport motor protein; primary cilia; 1-Indanone
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-022-00937-z

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.