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Updated: Jun 22, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury
Bruce A Molitoris1, Pierre C Dagher, Ruben M Sandoval
1Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. bmolitor@iupui.edu
Abstract:
Proximal tubule cells (PTCs), which are the primary site of kidney injury associated with ischemia or nephrotoxicity, are the site of oligonucleotide reabsorption within the kidney. We exploited this property to test the efficacy of siRNA targeted to p53, a pivotal protein in the apoptotic pathway, to prevent kidney injury. Naked synthetic siRNA to p53 injected intravenously 4 h after ischemic injury maximally protected both PTCs and kidney function. PTCs were the primary site for siRNA uptake within the kidney and body. Following glomerular filtration, endocytic uptake of Cy3-siRNA by PTCs was rapid and extensive, and significantly reduced ischemia-induced p53 upregulation. The duration of the siRNA effect in PTCs was 24 to 48 h, determined by levels of p53 mRNA and protein expression. Both Cy3 fluorescence and in situ hybridization of siRNA corroborated a short t(1/2) for siRNA. The extent of renoprotection, decrease in cellular p53 and attenuation of p53-mediated apoptosis by siRNA were dose- and time-dependent. Analysis of renal histology and apoptosis revealed improved injury scores in both cortical and corticomedullary regions. siRNA to p53 was also effective in a model of cisplatin-induced kidney injury. Taken together, these data indicate that rapid delivery of siRNA to proximal tubule cells follows intravenous administration. Targeting siRNA to p53 leads to a dose-dependent attenuation of apoptotic signaling, suggesting potential therapeutic benefit for ischemic and nephrotoxic kidney injury.
Insights
Intravenous siRNA targeting p53 effectively protected kidney cells from injury by reducing apoptosis. This naked synthetic small interfering RNA (siRNA) demonstrated rapid uptake by proximal tubule cells, offering potential therapeutic benefits for kidney diseases.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Proximal tubule cells (PTCs) are central to kidney injury from ischemia or nephrotoxicity.
- PTCs are the primary site for oligonucleotide reabsorption in the kidney.
- p53 protein plays a critical role in the apoptotic pathway.
Purpose of the Study:
- To evaluate the efficacy of small interfering RNA (siRNA) targeting p53 to prevent kidney injury.
- To investigate the delivery and uptake of siRNA in kidney cells.
- To assess the therapeutic potential of p53-targeted siRNA for kidney diseases.
Main Methods:
- Intravenous administration of naked synthetic siRNA targeting p53 in rodent models of kidney injury.
- Assessment of siRNA uptake by proximal tubule cells using Cy3-labeled siRNA.
- Measurement of p53 mRNA and protein levels, apoptosis markers, and renal histology.
- Evaluation in both ischemic and cisplatin-induced kidney injury models.
Main Results:
- Intravenous siRNA targeting p53 maximally protected proximal tubule cells and kidney function post-ischemic injury.
- Proximal tubule cells demonstrated rapid and extensive endocytic uptake of siRNA following intravenous administration.
- siRNA treatment significantly reduced ischemia-induced p53 upregulation and p53-mediated apoptosis.
- Renal histology showed improved injury scores, and siRNA was effective in cisplatin-induced kidney injury.
Conclusions:
- Rapid delivery of siRNA to proximal tubule cells is achievable via intravenous administration.
- Targeting p53 with siRNA attenuates apoptotic signaling in a dose- and time-dependent manner.
- p53-targeted siRNA shows significant therapeutic potential for treating ischemic and nephrotoxic kidney injury.
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