dc.contributor.author |
Sander, Veronika |
en |
dc.contributor.author |
Digby, JLM |
en |
dc.contributor.author |
Przepiorski, AJ |
en |
dc.contributor.author |
Davidson, Alan |
en |
dc.coverage.spatial |
Washington DC, USA |
en |
dc.date.accessioned |
2020-06-08T00:34:21Z |
en |
dc.date.issued |
2019-11-05 |
en |
dc.identifier.issn |
1046-6673 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/51367 |
en |
dc.description.abstract |
BACKGROUND The clinical use of the chemotherapeutic drug cisplatin is limited by its severe nephrotoxic side effects. The development of reno-protective therapies for cisplatin-induced acute kidney injury (AKI) is hampered by a lack of understanding of cisplatin-mediated nephrotoxicity. In recent years, kidney organoids derived from human pluripotent stem cells have been proposed as a platform to study AKI. Here, we describe a comprehensive approach to test the applicability of kidney organoids to model cisplatin-induced AKI. METHODS Different doses of cisplatin were added to the culture medium of induced pluripotent stem cell-derived kidney organoids. Cisplatin-treated organoids along with controls were analysed for injury and inflammation markers by quantitative PCR, immunohistochemistry and antibody array. RESULTS We found that organoids treated with cisplatin display increased levels of the kidney injury marker KIM1, DNA damage and cell death in a dose-dependent manner. Co-localization of the DNA double-strand break marker yH2AX with the different cell types in the organoids revealed that cisplatin predominantly affects proliferating cells suggesting a general cytotoxic effect reminiscent of the drug’s impact on tumour cells. This result is contrary to cisplatin specifically damaging the proximal tubule in vivo. We measured low-level expression of proximal tubule-specific cisplatin transporters in organoids, providing one explanation for this observation. We further detected several AKI biomarkers and cytokines in the culture medium of cisplatin-treated organoids, consistent with the induction of an AKI-like inflammatory response. Notably, we observed peritubular accumulation of the injury biomarker Growth differentiation factor (GDF) 15 in cisplatin-treated organoids, and a worsening of cisplatin-induced injury when the organoids were co-treated with recombinant GDF15. CONCLUSION Our work validates the use of kidney organoids for modelling the inflammatory aspects of cisplatin-induced AKI and supports the potential of this human cell-based system for developing improved reno-protective therapies. |
en |
dc.description.uri |
https://www.asn-online.org/abstracts/ |
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dc.publisher |
American Society of Nephrology |
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dc.relation.ispartof |
Kidney Week 2019: American Society of Nephrology Annual Meeting |
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dc.relation.ispartofseries |
Journal of the American Society of Nephrology |
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dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
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dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
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dc.subject |
AKI |
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dc.subject |
kidney organoids |
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dc.subject |
cisplatin |
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dc.title |
Cisplatin Induces Inflammation and Secretion of AKI Biomarkers in Kidney Organoids |
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dc.type |
Conference Item |
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pubs.begin-page |
1083 |
en |
pubs.volume |
Abstract Supplement |
en |
dc.rights.holder |
Copyright: The author |
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pubs.author-url |
https://www.asn-online.org/education/kidneyweek/2019/program-abstract.aspx?controlId=3234095 |
en |
pubs.end-page |
1083 |
en |
pubs.finish-date |
2019-11-10 |
en |
pubs.publication-status |
Published online |
en |
pubs.start-date |
2019-11-05 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Abstract |
en |
pubs.elements-id |
800992 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Molecular Medicine |
en |
pubs.record-created-at-source-date |
2020-05-09 |
en |