Uuganbayar Udval, Ninomiya Hiromasa, Shimada Issei S, Yamada Chisato, Kanie Mayu, Kawai Shinji, Asai Takahiro, Miyoshi-Akiyama Toru, Itoh Masayuki, Hashimoto Yutaka, Kato Yoichi
Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
Department of Infection Diseases, National Center for Global Health and Medicine, Tokyo, Japan.
J Biol Chem. 2025 Jun 24;301(8):110413. doi: 10.1016/j.jbc.2025.110413.
CEP290 gene mutations are linked to Joubert syndrome-related disorders (JSRD) which present with various symptoms, including brain malformation, retinal degeneration, and kidney disorders. It remains unclear how patients with JSRD having CEP290 gene mutations lead to kidney disorders, particularly polycystic kidney disease including nephronophthisis (NPH). To address this question, Xenopus CEP290 (xCEP290) was depleted using morpholino oligonucleotides against xCEP290 in Xenopus embryos. xCEP290 morphants exhibited edema and dilated pronephric tubule, indicative of renal dysfunction. Next, RNA-seq analysis was performed to explore which signals and molecules are important for the formation of dilated pronephric tubule observed in the xCEP290 morphant kidney. The hallmark gene set associated with the IL-6/JAK/STAT3 signaling pathway was upregulated in xCEP290 morphant kidney, and inhibition of this signaling by JAK inhibitor ruxolitinib suppressed the dilated pronephric tubule in xCEP290 morphants. Furthermore, the expression level of transcription factor Xenopus FOSL1 (xFOSL1), whose gene expression is regulated by IL-6 signaling, was upregulated in xCEP290 morphant kidney, and overexpression of xFOSL1 induced pronephric tubular dilation. These results together revealed that abnormal activation of IL-6/JAK/STAT3/FOSL1 signal axis is responsible for dilated pronephric tubule resembling cystic lesions observed in polycystic kidney disease of JSRD patients with CEP290 gene mutations.
CEP290基因突变与约伯综合征相关疾病（JSRD）有关，这些疾病表现出各种症状，包括脑畸形、视网膜变性和肾脏疾病。目前尚不清楚携带CEP290基因突变的JSRD患者如何导致肾脏疾病，特别是包括肾单位肾痨（NPH）在内的多囊肾病。为了解决这个问题，在非洲爪蟾胚胎中使用针对非洲爪蟾CEP290（xCEP290）的吗啉代寡核苷酸来敲低xCEP290。xCEP290基因敲降胚胎表现出水肿和扩张的前肾小管，这表明存在肾功能障碍。接下来，进行RNA测序分析，以探索哪些信号和分子对在xCEP290基因敲降胚胎的肾脏中观察到的扩张前肾小管的形成很重要。与IL-6/JAK/STAT3信号通路相关的标志性基因集在xCEP290基因敲降胚胎的肾脏中上调，并且JAK抑制剂鲁索替尼对该信号的抑制作用抑制了xCEP290基因敲降胚胎中扩张的前肾小管。此外，转录因子非洲爪蟾FOSL1（xFOSL1）的表达水平在xCEP290基因敲降胚胎的肾脏中上调，其基因表达受IL-6信号调节，并且xFOSL1的过表达诱导了前肾小管扩张。这些结果共同表明，IL-6/JAK/STAT3/FOSL1信号轴的异常激活导致了类似于在携带CEP290基因突变的JSRD患者多囊肾病中观察到的囊性病变的扩张前肾小管。
