PMID- 32150447
OWN - NLM
STAT- MEDLINE
DCOM- 20200714
LR  - 20210402
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 318
IP  - 4
DP  - 2020 Apr 1
TI  - Evaluation of cisplatin-induced injury in human kidney organoids.
PG  - F971-F978
LID - 10.1152/ajprenal.00597.2019 [doi]
AB  - 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 microM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C 
      motif chemokine ligand 8 (CXCL8) expression, DNA damage (gammaH2AX), 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 tubule-specific SLC22A2/organic cation transporter 2 
      (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose 
      regimen of 4 x 5 microM 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 AKI biomarkers and develop better therapies.
FAU - Digby, Jenny L M
AU  - Digby JLM
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland, 
      New Zealand.
FAU - Vanichapol, Thitinee
AU  - Vanichapol T
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland, 
      New Zealand.
FAU - Przepiorski, Aneta
AU  - Przepiorski A
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland, 
      New Zealand.
FAU - Davidson, Alan J
AU  - Davidson AJ
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland, 
      New Zealand.
FAU - Sander, Veronika
AU  - Sander V
AUID- ORCID: 0000-0002-2918-833X
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland, 
      New Zealand.
LA  - eng
GR  - R01 DK069403/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20200309
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CXCL8 protein, human)
RN  - 0 (H2AX protein, human)
RN  - 0 (HAVCR1 protein, human)
RN  - 0 (Hepatitis A Virus Cellular Receptor 1)
RN  - 0 (Histones)
RN  - 0 (Interleukin-8)
RN  - 0 (Organic Cation Transporter 2)
RN  - 0 (SLC22A2 protein, human)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Acute Kidney Injury/*chemically induced/genetics/metabolism/pathology
MH  - Antineoplastic Agents/metabolism/*toxicity
MH  - Cells, Cultured
MH  - Cisplatin/metabolism/*toxicity
MH  - *DNA Damage
MH  - Dose-Response Relationship, Drug
MH  - Hepatitis A Virus Cellular Receptor 1/genetics/metabolism
MH  - Histones/metabolism
MH  - Humans
MH  - Interleukin-8/genetics/metabolism
MH  - Kidney Tubules, Proximal/*drug effects/metabolism/pathology
MH  - Organic Cation Transporter 2/metabolism
MH  - Organoids/*drug effects/metabolism/pathology
MH  - Time Factors
PMC - PMC7395477
OTO - NOTNLM
OT  - acute kidney injury
OT  - acute kidney injury biomarker
OT  - cisplatin
OT  - cytokine
OT  - inflammation
OT  - kidney organoids
OT  - nephrotoxicity
OT  - proximal tubule
OT  - repeated low-dose regimen
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2020/03/10 06:00
MHDA- 2020/07/15 06:00
PMCR- 2021/04/01
CRDT- 2020/03/10 06:00
PHST- 2020/03/10 06:00 [pubmed]
PHST- 2020/07/15 06:00 [medline]
PHST- 2020/03/10 06:00 [entrez]
PHST- 2021/04/01 00:00 [pmc-release]
AID - F-00597-2019 [pii]
AID - 10.1152/ajprenal.00597.2019 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2020 Apr 1;318(4):F971-F978. doi: 
      10.1152/ajprenal.00597.2019. Epub 2020 Mar 9.