Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.
Nat Commun. 2024 May 1;15(1):3698. doi: 10.1038/s41467-024-48025-6.
Mouse models of autosomal dominant polycystic kidney disease (ADPKD) show that intact primary cilia are required for cyst growth following the inactivation of polycystin-1. The signaling pathways underlying this process, termed cilia-dependent cyst activation (CDCA), remain unknown. Using translating ribosome affinity purification RNASeq on mouse kidneys with polycystin-1 and cilia inactivation before cyst formation, we identify the differential 'CDCA pattern' translatome specifically dysregulated in kidney tubule cells destined to form cysts. From this, Glis2 emerges as a candidate functional effector of polycystin signaling and CDCA. In vitro changes in Glis2 expression mirror the polycystin- and cilia-dependent changes observed in kidney tissue, validating Glis2 as a cell culture-based indicator of polycystin function related to cyst formation. Inactivation of Glis2 suppresses polycystic kidney disease in mouse models of ADPKD, and pharmacological targeting of Glis2 with antisense oligonucleotides slows disease progression. Glis2 transcript and protein is a functional target of CDCA and a potential therapeutic target for treating ADPKD.
常染色体显性遗传多囊肾病（ADPKD）的小鼠模型表明，在多囊蛋白-1失活后，完整的初级纤毛对于囊肿生长是必需的。这一过程的信号通路被称为纤毛依赖性囊肿激活（CDCA），但其具体机制仍不清楚。我们在囊肿形成前通过对具有多囊蛋白-1和纤毛失活的小鼠肾脏进行核糖体亲和纯化 RNA 测序（translating ribosome affinity purification RNASeq），鉴定出了在即将形成囊肿的肾小管细胞中特异性失调的差异“CDCA 模式”转录组。由此，Gli 家族锌指 2（Glis2）作为多囊蛋白信号和 CDCA 的候选功能效应物出现。Gli2 表达的体外变化反映了在肾组织中观察到的多囊蛋白和纤毛依赖性变化，验证了 Gli2 作为与囊肿形成相关的多囊蛋白功能的基于细胞培养的标志物。Gli2 的失活抑制了 ADPKD 小鼠模型中的多囊肾病，并且使用反义寡核苷酸对 Glis2 的药理学靶向治疗减缓了疾病进展。Glis2 转录本和蛋白是 CDCA 的功能靶点，也是治疗 ADPKD 的潜在治疗靶点。
