Department of Internal Medicine, Yale University, New Haven, Connecticut.
Department of Pathology, Yale University, New Haven, Connecticut.
J Am Soc Nephrol. 2021 Jan;32(1):41-51. doi: 10.1681/ASN.2020040511. Epub 2020 Oct 12.
Mutations in and , which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood.
Unbiased transcriptional profiling in an adult-onset mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and double-knockout mice that are protected from cyst growth served as controls.
The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. appeared as a central component in this analysis. expression was similarly dysregulated in models of ADPKD, and conditional inactivation of with markedly improved the cystic phenotype and kidney function compared with inactivation of alone. The / double knockout blocked cyst cell proliferation that otherwise accompanied inactivation alone.
Dysregulation of is an early driver of cyst cell proliferation in ADPKD due to inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of .
分别编码跨膜蛋白多囊蛋白-1 和多囊蛋白-2 的 和 基因突变导致常染色体显性多囊肾病（ADPKD）。多囊蛋白在初级纤毛中表达，纤毛结构的破坏显著减缓了多囊蛋白失活后 ADPKD 的进展。ADPKD 中多囊蛋白和纤毛依赖性囊肿进展的细胞机制仍不完全清楚。
在囊肿形成前的成年发病 小鼠模型中进行无偏转录谱分析，揭示了 单敲除肾脏中显著差异表达的基因（DEGs），这些基因被用于鉴定候选途径在注定形成囊肿的肾脏中失调。 研究验证了候选途径在 ADPKD 进展中的作用。野生型和 双敲除小鼠作为对照，它们免受囊肿生长的影响。
RNASeq 数据将细胞增殖确定为最失调的途径，其中与细胞周期功能相关的 241 个 DEGs 中有 15 个。 在这项分析中表现为一个核心组成部分。 在 ADPKD 的模型中表达也同样失调，与单独失活 相比，与 条件性失活 显著改善了囊肿表型和肾功能。 / 双敲除阻止了否则伴随 单独失活的囊肿细胞增殖。
由于 失活， 的失调是 ADPKD 中囊肿细胞增殖的早期驱动因素。针对囊肿细胞增殖的选择性靶向是减缓由 失活引起的 ADPKD 进展的有效方法。
