1-Indanone retards cyst development in ADPKD mouse model by stabilizing tubulin and down-regulating anterograde transport of cilia
1-Indanone retards cyst development in ADPKD mouse model by stabilizing tubulin and down-regulating anterograde transport of cilia
复制标题
1-茚满酮通过稳定微管蛋白和下调纤毛顺行运输来延缓 ADPKD 小鼠模型中囊肿的发育
DOI：
10.1038/s41401-022-00937-z
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Bao-xue Yang
中科院分区：
文献类型：
--
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
常染色体显性遗传性多囊肾病（ADPKD）是最常见的遗传性肾病。ADPKD囊肿的发生与上皮细胞的异常增殖有关，而上皮细胞的异常增殖受初级纤毛介导的上皮细胞信号转导的影响。因此，原纤毛被认为是ADPKD的治疗靶点。由于ADPKD表现出许多与实体瘤相似的病理特征，我们研究了使用抗肿瘤药物靶向初级纤毛是否可以减轻ADPKD的发展。采用MDCK囊肿模型筛选出24个具有抗肿瘤活性的天然化合物，其中1-茚酮对肾囊肿生长有明显的抑制作用，且无细胞毒性。该化合物还抑制胚胎肾囊肿模型中的囊肿发育。在新生的肾脏特异性Pkd 1基因敲除小鼠中，1-茚酮显着减缓肾脏肿大和囊肿扩张。此外，我们证明，1-茚酮抑制异常延长的囊性上皮纤毛促进微管蛋白聚合和显著下调表达的顺行运输马达蛋白KIF 3A和IFFT 88。此外，我们发现1-茚酮显著下调纤毛协调的Wnt/β-catenin，Hedgehog信号通路。这些结果表明，1-茚酮通过减少囊性上皮细胞中异常延长的纤毛长度来抑制囊性细胞增殖，表明1-茚酮可能具有延缓ADPKD囊肿发展的治疗潜力。
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.
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作者：
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通讯作者：
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