論文 - 詳細
| RRC ID | 85810 |
|---|---|
| 著者 | Suzuki T, Susa K, Kikuchi H, Nakano Y, Yanagi T, Hara Y, Fujiki T, Ando F, Mandai S, Mori Y, Mori T, Iwasa H, Hata Y, Uchida S, Sohara E. |
| タイトル | iPSC-based drug discovery identified the Hippo signaling pathway as a therapeutic target in the fibrosis of NPHP1-deficient nephronophthisis. |
| ジャーナル | Stem Cell Res Ther |
| Abstract |
BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS:Hippo signaling pathway is involved in the fibrotic changes associated with NPHP1-deficient NPH and the Hippo pathway inhibitors could be therapeutic agents. CLINICAL TRIAL NUMBER:Not applicable. |
| 巻・号 | 16(1) |
| ページ | 489 |
| 公開日 | 2025-9-19 |
| DOI | 10.1186/s13287-025-04567-0 |
| PII | 10.1186/s13287-025-04567-0 |
| PMID | 40968381 |
| PMC | PMC12447615 |
| MeSH | Adaptor Proteins, Signal Transducing* / deficiency Adaptor Proteins, Signal Transducing* / genetics Adaptor Proteins, Signal Transducing* / metabolism Cytoskeletal Proteins Drug Discovery* Fibrosis Hippo Signaling Pathway Humans Induced Pluripotent Stem Cells* / cytology Induced Pluripotent Stem Cells* / drug effects Induced Pluripotent Stem Cells* / metabolism Interleukin-1beta / pharmacology Kidney / metabolism Kidney / pathology Kidney Diseases, Cystic* / drug therapy Kidney Diseases, Cystic* / genetics Kidney Diseases, Cystic* / metabolism Kidney Diseases, Cystic* / pathology Organoids / drug effects Organoids / metabolism Organoids / pathology Protein Serine-Threonine Kinases* / antagonists & inhibitors Protein Serine-Threonine Kinases* / metabolism Signal Transduction / drug effects |
| IF | 5.116 |
| リソース情報 | |
| ヒト・動物細胞 | 1231A3(HPS0381) |