Stem cell research & therapy · 2025
iPSC-based drug discovery identified the Hippo signaling pathway as a therapeutic target in the fibrosis of NPHP1-deficient nephronophthisis.
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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
Аннотация
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.
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.