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@ARTICLE{Eckert:303491,
      author       = {P. Eckert and M. Nöller and M. Müller and R. Haas and J.
                      Ruf and H. Franz and K. Moos and J.-A. Yu and D. Zhao and W.
                      Xie and M. Boerries$^*$ and G. Walz and T. A. Yakulov},
      title        = {{T}argeting {GLP}-1 {S}ignaling {A}meliorates
                      {C}ystogenesis in a {Z}ebrafish {M}odel of
                      {N}ephronophthisis.},
      journal      = {International journal of molecular sciences},
      volume       = {26},
      number       = {15},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2025-01682},
      pages        = {7366},
      year         = {2025},
      abstract     = {Nephronophthisis (NPH) is the leading genetic cause of
                      end-stage renal disease in children and young adults, but no
                      effective disease-modifying therapies are currently
                      available. Here, we identify glucagon-like peptide-1 (GLP-1)
                      signaling as a novel therapeutic target for NPH through a
                      systematic drug repurposing screen in zebrafish. By
                      simultaneously depleting nphp1 and nphp4, we developed a
                      robust zebrafish model that reproduces key features of human
                      NPH, including glomerular cyst formation. Our screen
                      revealed that dipeptidyl peptidase-4 (DPP4) inhibitors
                      (Omarigliptin and Linagliptin) and GLP-1 receptor agonists
                      (Semaglutide) significantly reduce cystogenesis in a
                      dose-dependent manner. Genetic analysis demonstrated that
                      GLP-1 receptor signaling is important for maintaining
                      pronephros integrity, with gcgra and gcgrb (GLP-1 receptor
                      genes) playing a particularly important role. Transcriptomic
                      profiling identified adenosine receptor A2ab (adora2ab) as a
                      key downstream effector of GLP-1 signaling, which regulates
                      ciliary morphology and prevents cyst formation. Notably,
                      nphp1/nphp4 double mutant zebrafish exhibited the
                      upregulation of gcgra as a compensatory mechanism, which
                      might explain their resistance to cystogenesis. This
                      compensation was disrupted by the targeted depletion of
                      GLP-1 receptors or the inhibition of adenylate cyclase,
                      resulting in enhanced cyst formation, specifically in the
                      mutant background. Our findings establish a signaling
                      cascade from GLP-1 receptors to adora2ab in terms of
                      regulating ciliary organization and preventing cystogenesis,
                      offering new therapeutic opportunities for NPH through the
                      repurposing of FDA-approved medications with established
                      safety profiles.},
      keywords     = {GLP-1 signaling (Other) / adenosine receptor (Other) /
                      adenylate cyclase (Other) / cystogenesis (Other) /
                      nephronophthisis (Other) / zebrafish (Other)},
      cin          = {FR01},
      ddc          = {540},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40806500},
      doi          = {10.3390/ijms26157366},
      url          = {https://inrepo02.dkfz.de/record/303491},
}