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Patient-derived kidney organoids recapitulate ADPKD and enable the identification of RHO signaling inhibitors as candidate therapeutics [RNA-Seq]

ABSTRACT: Current renal organoid models, typically derived from pluripotent stem cells, recapitulate aspects of kidney development but are constrained by cellular immaturity and off-target populations. Here, we establish an expandable renal organoid system from adult patient kidney tissues, comprising proliferative epithelial progenitors and differentiated proximal tubule and collecting duct lineages. Leveraging this system, we generated “petal-like” polycystic organoids from PKD1 or PKD2 mutant tissues that faithfully mimic the morphological and functional hallmarks of ADPKD. Mechanistic investigation revealed that RHO signaling may serve as a candidate component of the cilia-dependent cyst activation (CDCA) mechanism that drives cystogenesis. Subsequent drug screening identified RHO GTPase inhibitors as selective suppressors of cyst growth across multiple organoid lines. This patient tissue-derived organoid platform offers a physiologically relevant and robust model for investigating cytogenic mechanisms and enabling precision therapeutic discovery and drug screen in polycystic kidney disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296369 | GEO | 2025/05/15

REPOSITORIES: GEO

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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.

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Patient-derived kidney organoids recapitulate ADPKD and enable the identification of RHO signaling inhibitors as candidate therapeutics [RNA-Seq]

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