Eckert Priska, Nöller Maike, Müller Merle, Haas Rebecca, Ruf Johannes, Franz Henriette, Moos Katharina, Yu Jia-Ao, Zhao Dongfang, Xie Wanqiu, Boerries Melanie, Walz Gerd, Yakulov Toma A
Renal Division, University Freiburg Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Department of Biomedicine, University of Basel, 4001 Basel, Switzerland.
Int J Mol Sci. 2025 Jul 30;26(15):7366. doi: 10.3390/ijms26157366.
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 and , 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 and (GLP-1 receptor genes) playing a particularly important role. Transcriptomic profiling identified adenosine receptor A2ab () as a key downstream effector of GLP-1 signaling, which regulates ciliary morphology and prevents cyst formation. Notably, double mutant zebrafish exhibited the upregulation of 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 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.
肾单位肾痨（NPH）是儿童和青年终末期肾病的主要遗传病因，但目前尚无有效的疾病改善疗法。在此，我们通过在斑马鱼中进行系统的药物再利用筛选，确定胰高血糖素样肽-1（GLP-1）信号通路是NPH的一个新的治疗靶点。通过同时敲除 和 ，我们建立了一个强大的斑马鱼模型，该模型再现了人类NPH的关键特征，包括肾小球囊肿形成。我们的筛选显示，二肽基肽酶-4（DPP4）抑制剂（奥格列汀和利那格列汀）和GLP-1受体激动剂（司美格鲁肽）以剂量依赖的方式显著减少囊肿形成。基因分析表明，GLP-1受体信号通路对于维持前肾完整性很重要，其中 和 （GLP-1受体基因）发挥着特别重要的作用。转录组分析确定腺苷受体A2ab（ ）是GLP-1信号通路的关键下游效应器，其调节纤毛形态并防止囊肿形成。值得注意的是， 双突变斑马鱼表现出 上调作为一种补偿机制，这可能解释了它们对囊肿形成的抗性。这种补偿被GLP-1受体的靶向敲除或腺苷酸环化酶抑制所破坏，导致囊肿形成增加，特别是在突变背景下。我们的研究结果建立了从GLP-1受体到 在调节纤毛组织和防止囊肿形成方面的信号级联，通过重新利用具有既定安全性的FDA批准药物为NPH提供了新的治疗机会。
