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Abstract: FR-PO577

Organoid Model of Polycystic Kidney Disease Recapitulates Clinically Relevant Symptoms and Identifies Candidate Drugs

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Liu, Meng, Nanyang Technological University, Singapore, Singapore, Singapore
  • Zhang, Chao, Nanyang Technological University, Singapore, Singapore, Singapore
  • Zhang, Tian, Nanyang Technological University, Singapore, Singapore, Singapore
  • Cardilla, Angelysia, Nanyang Technological University, Singapore, Singapore, Singapore
  • Xia, Yun, Nanyang Technological University, Singapore, Singapore, Singapore
Background

Polycystic kidney disease (PKD) is one of the most common genetic kidney diseases, characterized by the progressive expansion of fluid-filled cysts in the kidney. Currently, there are limited treatment approaches for PKD. Advances in generating kidney organoids from human pluripotent stem cells (hPSCs) have helped overcome many of the drawbacks of the traditional mouse and 2D cell culture models. Alongside genetic editing, these organoids have been used to investigate the pathogenic mechanisms of PKD and to screen for potential drugs.

Methods

Herein, we have generated a collection of kidney organoids from both ARPKD and ADPKD patient-derived iPSCs, as well as genetically engineered hPSCs. Subsequently, we employed stress paradigms to modulate intracellular levels of cAMP or Ca2+ for inducing cystogenesis. We further characterized the structural and functional abnormalities in PKD kidney organoids using a multitude of analyses, including cell biology, molecular biology, biochemistry, and single nuclei RNA-sequencing. Finally, we performed a small-scale drug screening to identify candidate drugs.

Results

PKD kidney organoids developed tubular cysts in response to upregulation of intracellular cAMP or downregulation of Ca2+ homeostasis. Multiple structural and functional abnormalities were observed in PKD organoids, including hyper-proliferation of cystic epithelial cells, increased fluid secretion, tubular injury and dedifferentiation, as well as aberrant renin release which are commonly observed in PKD patients. Employing cystic index as the readout, we identified two candidate drugs that can effectively attenuate cyst formation in PKD organoids.

Conclusion

hPSCs derived organoid model of PKD can faithfully recapitulate critical structural and functional characteristics of PKD which would serve as an invaluable tool to investigate PKD pathogenesis and to discover potential therapeutics.

Funding

  • Government Support – Non-U.S.