Journal Article

Targeting GLP-1 Signaling Ameliorates Cystogenesis in a Zebrafish Model of Nephronophthisis

Ruf, Johannes, Franz, Henriette, Boerries, Melanie, Zhao, Dongfang, Yakulov, Toma A., Haas, Rebecca, Walz, Gerd, Eckert, Priska, Yu, Jia-ao, Nöller, Maike, Xie, Wanqiu, Müller, Merle, Moos, Katharina

2025

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Adenosine / Agonists / Animals / Cell cycle / Cysts / Dipeptidyl-Peptidase IV Inhibitors - pharmacology / Disease Models, Animal / Drug dosages / Drug Repositioning / Embryos / Genotype & phenotype / GLP-1 receptor agonists / Glucagon / Glucagon-Like Peptide 1 - metabolism / Glucagon-Like Peptide-1 Receptor - genetics / Glucagon-Like Peptide-1 Receptor - metabolism / Humans / Inflammation / Kidney diseases / Localization / Mutation / Signal Transduction - drug effects / Zebrafish / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism