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

Area of Science:

• Genetics
• Nephrology
• Pharmacology

Background:

• Nephronophthisis (NPH) is a primary genetic cause of kidney failure in pediatric and young adult populations.
• Currently, no effective therapies exist to modify the progression of NPH.
• Drug repurposing presents a viable strategy for identifying novel NPH treatments.

Purpose of the Study:

• To identify novel therapeutic targets for NPH through drug repurposing.
• To investigate the role of glucagon-like peptide-1 (GLP-1) signaling in NPH pathogenesis.
• To establish a signaling pathway regulating ciliary function in NPH.

Main Methods:

• Developed a zebrafish model of NPH by depleting nphp1 and nphp4 genes.
• Conducted a systematic drug repurposing screen using the NPH zebrafish model.
• Utilized genetic analysis, transcriptomic profiling, and pharmacological interventions.

Main Results:

• GLP-1 receptor agonists (Semaglutide) and DPP4 inhibitors (Omarigliptin, Linagliptin) significantly reduced cystogenesis in NPH zebrafish.
• GLP-1 receptor signaling, particularly via gcgra and gcgrb, is crucial for maintaining kidney integrity.
• Adenosine receptor A2ab (adora2ab) acts as a downstream effector of GLP-1 signaling, regulating ciliary morphology and preventing cyst formation.

Conclusions:

• GLP-1 signaling represents a promising therapeutic target for NPH.
• A signaling cascade involving GLP-1 receptors and adora2ab regulates ciliary organization and prevents cystogenesis.
• Repurposing FDA-approved GLP-1-related medications offers a potential therapeutic strategy for NPH.