期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 318, 期 4, 页码 F971-F978出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00597.2019
关键词
acute kidney injury; acute kidney injury biomarker; cisplatin; cytokine; inflammation; kidney organoids; nephrotoxicity; proximal tubule; repeated low-dose regimen
资金
- Health Research Council of New Zealand [17/425]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-069403]
- United States Army Medical Research and Development Command [W81XWH-17-1-0610]
Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human -based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell -derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 M cisplatin induces hepatitis A virus cellular receptor I (HAVCRI) and C -X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage VyII2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubulespecific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low -dose regimen of 4 X 5 M cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AK.I. biomarkers and develop better therapies.
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