PUBLICATION
Targeting GLP-1 Signaling Ameliorates Cystogenesis in a Zebrafish Model of Nephronophthisis
- Authors
- Eckert, P., Nöller, M., Müller, M., Haas, R., Ruf, J., Franz, H., Moos, K., Yu, J.A., Zhao, D., Xie, W., Boerries, M., Walz, G., Yakulov, T.A.
- ID
- ZDB-PUB-250814-19
- Date
- 2025
- Source
- International Journal of Molecular Sciences 26: (Journal)
- Registered Authors
- Keywords
- GLP-1 signaling, adenosine receptor, adenylate cyclase, cystogenesis, nephronophthisis, zebrafish
- Datasets
- GEO:GSE291774, GEO:GSE291847
- MeSH Terms
-
- Drug Repositioning
- Glucagon-Like Peptide 1*/metabolism
- Glucagon-Like Peptide-1 Receptor/genetics
- Glucagon-Like Peptide-1 Receptor/metabolism
- Disease Models, Animal
- Humans
- Zebrafish
- Signal Transduction*/drug effects
- Dipeptidyl-Peptidase IV Inhibitors/pharmacology
- Animals
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 40806500 Full text @ Int. J. Mol. Sci.
Citation
Eckert, P., Nöller, M., Müller, M., Haas, R., Ruf, J., Franz, H., Moos, K., Yu, J.A., Zhao, D., Xie, W., Boerries, M., Walz, G., Yakulov, T.A. (2025) Targeting GLP-1 Signaling Ameliorates Cystogenesis in a Zebrafish Model of Nephronophthisis. International Journal of Molecular Sciences. 26:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping