Abstract: FR-PO248

Kidney Organoids Replicate Drug-Induced AKI in a Segment-Specific Manner

Session Information

  • Stem Cells
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Developmental Biology and Inherited Kidney Diseases

  • 402 Stem Cells

Authors

  • Susa, Koichiro, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Gupta, Navin R., Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Morizane, Ryuji, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Drug-induced kidney injury is a serious problem in clinical settings and a major barrier to development of new drug candidates. Many nephrotoxicants are taken up into the cytoplasm through renal drug transporters such as organic cation/anion transporters (OCTs and OATs). These transporters, however, are generally not expressed in cell lines of immortalized human kidney tubules, a fact that markedly limits clinical translatability of drug screening systems in vitro. Recently, kidney organoids containing multi-segmented nephron epithelial cells have been generated from human pluripotent stem cells. These can to be used for drug screening as a novel technology using human cells.

Methods

Kidney organoids were differentiated from human ES and iPS cells by a previously established protocol. Organoids were exposed to various nephrotoxicants which induces segment specific injury: cisplatin, aristolochic acid (AA), tenofovir, puromycin aminonucleoside (PAN), adriamycin, and lithium. Drug transporter expression and kidney injury in organoids were evaluated by qRT-PCR and immunostaining and compared to a human kidney tubular cell line (HKC-8).

Results

qRT-PCR demonstrated marked expression of OCT2, OAT1 and 3, which are major renal drug transporters, in kidney organoids while HKC-8 cells showed much lower expression of these transporters. The organoids showed upregulated tubular injury markers such as KIM-1 and L-FABP after treatment with cisplatin, tenofovir, or AA, but not by PAN or lithium. Cimetidine and probenecid, which are inhibitors of OCT2 or OATs respectively, ameliorated the injury caused by cisplatin or tenofovir. Lithium caused significantly decreased expression of aquaporin 2 in kidney organoids. PAN and adriamycin induced severe morphological injury and decreased expression of nephrin in glomerulus-like structures of organoids, whereas cisplatin did not. On the other hand, HKC-8 treated with those nephrotoxicants did not exhibit significant change of tubular injury markers.

Conclusion

Kidney organoids faithfully mimic drug-induced tubular and glomerular injury, suggesting they will be useful for evaluation of nephrotoxicity of drugs and substantially superior to conventional nephrotoxicity screening method using cultured cells.

Funding

  • NIDDK Support