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Updated: Apr 28, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Cisplatin-induced renal injury is independently mediated by OCT2 and p53
Jason A Sprowl1, Cynthia S Lancaster1, Navjotsingh Pabla1
1Departments of Pharmaceutical Sciences and.
Purpose:
Tubular secretion of cisplatin is abolished in mice deficient for the organic cation transporters Oct1 and Oct2 (Oct1/2(-/-)mice), and these animals are protected from severe cisplatin-induced kidney damage. Since tubular necrosis is not completely absent in Oct1/2(-/-)mice, we hypothesized that alternate pathways are involved in the observed injury.
Experimental Design:
Studies were done in wild-type, Oct1/2(-/-), or p53-deficient animals, all on an FVB background, receiving cisplatin intraperitoneally at 15 mg/kg. Cisplatin metabolites were analyzed using mass spectrometry, and gene expression was assessed using Affymetrix microarrays and RT-PCR arrays.
Results:
KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that the most significantly altered genes were associated with the p53 signaling network, including Cdnk1a and Mdm2, in both wild-type (P = 2.40 × 10(-11)) and Oct1/2(-/-)mice (P = 1.92 × 10(-8)). This was confirmed by demonstrating that homozygosity for a p53-null allele partially reduced renal tubular damage, whereas loss of p53 in Oct1/2(-/-)mice (p53(-/-)/Oct1/2(-/-)) completely abolished nephrotoxicity. We found that pifithrin-α, an inhibitor of p53-dependent transcriptional activation, inhibits Oct2 and can mimic the lack of nephrotoxicity observed in p53(-/-)/Oct1/2(-/-)mice.
Conclusions:
These findings indicate that (i) the p53 pathway plays a crucial role in the kidney in response to cisplatin treatment and (ii) clinical exploration of OCT2 inhibitors may not lead to complete nephroprotection unless the p53 pathway is simultaneously antagonized.
Insights
Cisplatin causes kidney damage partly through the p53 pathway. Blocking both organic cation transporter 2 (OCT2) and p53 completely prevents this nephrotoxicity in mice.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Cisplatin is a widely used chemotherapy agent with significant nephrotoxicity.
- Organic cation transporters, specifically OCT1 and OCT2, are involved in cisplatin secretion and kidney damage.
- Complete protection from cisplatin nephrotoxicity was not achieved by blocking OCT1/2 alone, suggesting alternative injury pathways.
Purpose of the Study:
- To investigate the role of alternate pathways in cisplatin-induced kidney injury, particularly in the absence of Oct1 and Oct2.
- To elucidate the involvement of the p53 signaling network in cisplatin nephrotoxicity.
Main Methods:
- Studies were conducted in wild-type, Oct1/2(-/-), and p53-deficient mice treated with cisplatin.
- Cisplatin metabolites were analyzed using mass spectrometry.
- Gene expression changes were assessed using microarrays and RT-PCR arrays.
Main Results:
- KEGG pathway analysis revealed significant alterations in the p53 signaling network in response to cisplatin in both wild-type and Oct1/2(-/-) mice.
- Loss of p53 partially reduced renal tubular damage in cisplatin-treated mice.
- Simultaneous deficiency of p53 and Oct1/2 completely abolished cisplatin-induced nephrotoxicity.
- Pifithrin-α, a p53 inhibitor, also reduced cisplatin nephrotoxicity.
Conclusions:
- The p53 pathway is a critical mediator of cisplatin nephrotoxicity in the kidney.
- Combined inhibition of OCT2 and the p53 pathway is necessary for complete protection against cisplatin-induced kidney damage.
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