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

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.