Suzuki Takefumi, Susa Koichiro, Kikuchi Hiroaki, Nakano Yuta, Yanagi Tomoki, Hara Yu, Fujiki Tamami, Ando Fumiaki, Mandai Shintaro, Mori Yutaro, Mori Takayasu, Iwasa Hiroaki, Hata Yutaka, Uchida Shinichi, Sohara Eisei
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Research and Development Division, Perseus Proteomics Inc, Tokyo, Japan.
Stem Cell Res Ther. 2025 Sep 19;16(1):489. doi: 10.1186/s13287-025-04567-0.
Nephronophthisis (NPH) is an autosomal recessive kidney disease, and NPHP1 is the most frequently affected gene. Tubulointerstitial fibrosis is the major phenotype of NPHP1-deficient NPH. The pathophysiology of NPHP1-deficient NPH is unclear because models representing the disease pathophysiology are lacking. Herein, we aimed to create a novel pathological model of NPH using 3D kidney organoids derived from human-induced pluripotent stem cells (iPSCs) and elucidated the pathophysiology while searching for therapeutic candidates.
NPHP1-deficient kidney organoids were generated from iPSCs. Fibrosis was induced by treatment with IL-1β. The effects of the Hippo signaling pathway inhibitors as therapeutic candidates were assessed. Fibrotic status was evaluated using immunofluorescence and quantitative PCR.
NPHP1 kidney organoids were generated from iPSCs. Fibrosis induction with IL-1β considerably increased the expression of fibronectin and transcription of fibrosis-related genes in NPHP1 organoids. Long-term culture of NPHP1 organoids induced substantial fibrogenesis compared with wild-type organoids. Co-immunoprecipitation analysis revealed the binding of NPHP1 to LATS1/2-the main constituents of the Hippo pathway. IL-1β administration increased the expression of the key Hippo pathway genes in NPHP1 organoids. By contrast, the Hippo pathway inhibitors ameliorated IL-1β-induced fibrogenesis in NPHP1 organoids. Because one of the inhibitors, verteporfin, is in clinical use, its practical availability is expected from a drug-repositioning perspective.
Hippo signaling pathway is involved in the fibrotic changes associated with NPHP1-deficient NPH and the Hippo pathway inhibitors could be therapeutic agents.
Not applicable.
肾单位肾痨（NPH）是一种常染色体隐性遗传性肾脏疾病，NPHP1是最常受累的基因。肾小管间质纤维化是NPHP1缺陷型NPH的主要表型。由于缺乏代表该疾病病理生理学的模型，NPHP1缺陷型NPH的病理生理学尚不清楚。在此，我们旨在利用源自人诱导多能干细胞（iPSC）的3D肾脏类器官创建一种新型的NPH病理模型，并在寻找治疗候选药物的同时阐明其病理生理学。
从iPSC生成NPHP1缺陷型肾脏类器官。用IL-1β处理诱导纤维化。评估作为治疗候选药物的Hippo信号通路抑制剂的作用。使用免疫荧光和定量PCR评估纤维化状态。
从iPSC生成了NPHP1肾脏类器官。用IL-1β诱导纤维化显著增加了NPHP1类器官中纤连蛋白的表达和纤维化相关基因的转录。与野生型类器官相比，NPHP1类器官的长期培养诱导了大量的纤维生成。免疫共沉淀分析揭示了NPHP1与Hippo通路的主要成分LATS1/2的结合。给予IL-1β增加了NPHP1类器官中关键Hippo通路基因的表达。相比之下，Hippo通路抑制剂改善了NPHP1类器官中IL-1β诱导的纤维生成。由于其中一种抑制剂维替泊芬正在临床使用，从药物重新定位的角度来看，有望实现其实际应用。
Hippo信号通路参与了与NPHP1缺陷型NPH相关的纤维化变化，Hippo通路抑制剂可能是治疗药物。
不适用。
