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Abstract: TH-PO218

Developing hPSC-Derived Kidney Organoid Model for Emulating Key Pathological Features of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Cardilla, Angelysia, Lee Kong Chian School of Medicine, Singapore, Singapore
  • Zhang, Tian, Lee Kong Chian School of Medicine, Singapore, Singapore
  • Naik, Mihir Yogesh, Lee Kong Chian School of Medicine, Singapore, Singapore
  • Xia, Yun, Lee Kong Chian School of Medicine, Singapore, Singapore
Background

Diabetic nephropathy (DN) represents one of the leading causes of end-stage renal disease (ESRD). Current treatment of DN focuses primarily on controlling physiological symptoms without retarding or reversing disease progression. To date, most DN studies are based on animal models, though there is a major concern on how closely the animal models mimic human pathophysiology. A new DN model that presents higher relevance with human physiology is urgently needed to better understand the disease mechanisms of DN and to discover effective therapeutics.

Methods

In the past decades, organoids have become a powerful tool for modeling human diseases due to their ability to recapitulate the complexity of human organs. Here, we used state-of-the-art kidney organoid technology to emulate pathogenesis of diabetic nephropathy. Kidney organoids are derived in vitro from human pluripotent stem cells (hPSCs), harboring segmentally patterned nephron-like structures and stroma, as well as a vascular network. To emulate DN phenotypes, we exposed hPSC-derived kidney organoids to stress paradigms that are presented in pre-diabetic and diabetic states. We performed histopathological and functional analysis to evaluate organoid pathology under these conditions.

Results

Within diabetic kidney organoids, we observed multiple phenotypes that are characteristic of DN, including altered tissue architecture and compromised functionality. Particularly, the existence of an intrinsic vascular network enabled us to interrogate the deterioration of renal vasculature during the development of DN.

Conclusion

The new human stem cell-based kidney organoid model will allow us to study DN pathogenesis in vitro as well as in vivo, leading to identification of novel therapeutic agents with higher clinical potential.