Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting GLP-1 signaling ameliorates cystogenesis in a zebrafish model of nephronophthisis

ABSTRACT: Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, with no effective disease-modifying therapies 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 recapitulates 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 upregulation of gcgra as a compensatory mechanism, explaining their resistance to cystogenesis. This compensation was disrupted by targeted depletion of GLP-1 receptors or 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 regulating ciliary organization and preventing cystogenesis, offering new therapeutic opportunities for NPH through repurposing of FDA-approved medications with established safety profiles.

ORGANISM(S): Danio rerio

PROVIDER: GSE291847 | GEO | 2025/08/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcriptome analysis of nphp1(ex15-del4); nphp4(sa38686) double mutant zebrafish

Project description:Nephronophthisis (NPH) is the most common genetic cause of end-stage renal disease in children and young adults. Mutations in more than 25 genes, called NPHPs, were found to be causative. We performed RNA sequencing analysis to investigate the transcriptional changes in nphp1(ex15-del4); nphp4(sa38686) homozygous mutant zebrafish compared to wild-type siblings. Our analysis revealed significant alterations in gene expression profiles associated with cilia function, cell signaling pathways, and kidney development. This dataset provides insights into the molecular mechanisms underlying NPH pathogenesis and genetic compensation in a zebrafish model of the disease.

2025-08-01 | GSE291774 | GEO

Transcriptome analysis of nphp1(ex15-del4) nphp4(sa38686) double mutant zebrafish

Project description:Transcriptome analysis of nphp1(ex15-del4) nphp4(sa38686) double mutant zebrafish

| PRJNA1235224 | ENA

Variable phenotypes and penetrance between and within different zebrafish transition zone mutants

Project description:Meckel Syndrome, Nephronophthisis, Joubert Syndrome, and Bardet-Biedl Syndrome have mutations in proteins that localize to the ciliary transition zone (TZ). The phenotypically distinct syndromes suggest these TZ proteins have differing functions. However, mutations in a single TZ gene can result in multiple syndromes suggesting the phenotype is influenced by modifier genes. We performed a comprehensive analysis of ten zebrafish TZ mutants including mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1, and nphp4, as well as mutants in ift88 and ift172. Our data indicate variations in phenotypes exists between different TZ mutants, supporting different tissue specific functions of these TZ genes. Further we observed phenotypic variations within progeny of a single TZ mutant, reminiscent of multiple disease syndromes being associated with mutations in one gene. In some mutants the dynamics of the phenotype became complex with transitory phenotypes that are corrected over time. We have also demonstrated that multiple-guide derived CRISPR/Cas9 F0 “Crispant” embryos recapitulate zygotic null phenotypes, and rapidly identified ciliary phenotypes in 11 cilia-associated gene candidates (ankfn1, ccdc65, cfap57, fhad1, nme7, pacrg, saxo2, c1orf194, ttc26, zmynd12, and cfap52).

2022-11-30 | GSE217001 | GEO

Confirmation of the gene expression pattern in Mxi1-deficient mouse

Project description:For final aim to completes network map between gene that is concerned in cystogenesis, verifies meaning genes connected with cyst formation analyzing gene pattern in Mxi1 KO mouse that have phenotype of polycystic kidney disease. Monitoring meaning genes through microarray analysis, and confirm the function of these genes. Also, find pathway including meaning genes and new pathway related with PKD. Completes network map concerned in cystogenesis through integrates knowing pathway and predicting pathway. Develope diagnostic of cyst disease and cure target through such completed network map, and wish to clear new role of cyst formation connection gene through in vivo model and examine closely control system of cyst formation mechanism. Keywords: Cystogenesis Use 1 mouse at each experiment and control. Indirect labeling of 10g cRNA, using bacterial control mRNA.

2008-04-29 | E-GEOD-11053 | biostudies-arrayexpress

Confirmation of the gene expression pattern in Mxi1-deficient mouse

2008-04-29 | GSE11053 | GEO

Confirmation of the gene expression pattern in Mxi1-deficient mouse (time course)

Project description:For final aim to completes network map between gene that is concerned in cystogenesis, verifies meaning genes connected with cyst formation analyzing gene pattern in time-dependent Mxi1 KO mouse that have phenotype of polycystic kidney disease. Monitoring meaning genes through microarray analysis, and confirm the function of these genes. Also, find pathway including meaning genes and new pathway related with PKD. Completes network map concerned in time-dependent cystogenesis through integrates knowing pathway and predicting pathway. Develope diagnostic of cyst disease and cure target through such completed network map, and wish to clear new role of cyst formation connection gene through in vivo model and examine closely control system of cyst formation mechanism. Keywords: time course Use 1 mouse at each time experiment and control(total 12 mice). Indirect labeling of 10g cRNA, using bacterial control mRNA.

2008-03-31 | E-GEOD-10941 | biostudies-arrayexpress

Confirmation of the gene expression pattern in Mxi1-deficient mouse (time course)

Project description:For final aim to completes network map between gene that is concerned in cystogenesis, verifies meaning genes connected with cyst formation analyzing gene pattern in time-dependent Mxi1 KO mouse that have phenotype of polycystic kidney disease. Monitoring meaning genes through microarray analysis, and confirm the function of these genes. Also, find pathway including meaning genes and new pathway related with PKD. Completes network map concerned in time-dependent cystogenesis through integrates knowing pathway and predicting pathway. Develope diagnostic of cyst disease and cure target through such completed network map, and wish to clear new role of cyst formation connection gene through in vivo model and examine closely control system of cyst formation mechanism. Keywords: time course

2008-03-31 | GSE10941 | GEO

Targeting GLP-1 signaling ameliorates cystogenesis in a zebrafish model of nephronophthisis

Project description:Targeting GLP-1 signaling ameliorates cystogenesis in a zebrafish model of nephronophthisis

| PRJNA1235623 | ENA

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (RNA-Seq)

Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.

2019-06-20 | GSE128522 | GEO

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (ChIP-Seq)

2019-06-20 | GSE128521 | GEO