Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure
Open accessAbstract
Background The p21 protein is found in the nucleus of most cells where it modulates cell cycle activity. At low levels, p21 stabilizes interactions between D cyclins and their cyclin-dependent kinases (cdks), but at high levels after induction by several different stress pathways, it causes cell cycle arrest. The p21 mRNA is induced in murine kidney after several types of acute renal failure, including cisplatin administration, ischemia-reperfusion, and ureteral obstruction. We reported that after cisplatin injection, mice with a p21 gene deletion developed much more severe renal damage than wild-type mice. To dissociate the effects of cisplatin-induced DNA damage and subsequent initiation of DNA damage-dependent cell death pathways from effects of acute renal failure, we have now examined mice after ischemia-reperfusion, a model of renal failure not associated with genotoxin-induced DNA damage early after the injury.Methods Wild-type and p21(-/-) mice were made ischemic by clamping both renal hila for 30 or 50 minutes. At various times after reflow, mortality and parameters of renal function and morphology were quantified. Also, the nuclear proteins p21 and proliferating cell nuclear antigen (PCNA) were localized in kidney sections by immunohistochemistry.Results Kidney function was more impaired and mortality increased significantly in p21(-/-) mice as compared with p21(+/+) mice. We found more cell cycle activity, indicated by increased number of mitotic cells and nuclear PCNA-positive cells, in kidney of p21(-/-) mice.Conclusions In this study, p21(-/-) mice were more susceptible to ischemia-induced acute renal failure, with similarly elevated levels of parameters of cell cycle activity. We propose that the increased and inappropriate cell cycle activity in kidney cells is responsible for the increased kidney impairment and mortality.
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After ischaemia-reperfusion injury in a murine model, nuclear p21 cip1 was localised in proximal and distal nephrons, but not in the glomerular area.
“In another murine model, after ischaemia-reperfusion injury, nuclear p21 cip1 (CDK-interacting protein 1) was localised in proximal and distal nephrons, but not in the glomerular area.101”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [101]
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- Authors
- Megyesi, J., Andrade, L., Vieira, J. M., Safirstein, R. L., & Price, P. M.
- Affiliations
- University of Arkansas Medical Center (US)
- University of Arkansas for Medical Sciences (US)
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2001-12
- Volume
- 60
- Issue
- 6
- Pages
- 2164-2172
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W1973959559
- Cited by
- 153
- References
- 45
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 15 · 2020: 11 · 2019: 4 · 2018: 8 · 2017: 5 · 2016: 7 · 2015: 5 · 2014: 10 · 2013: 2 · 2012: 5
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK054471, 5R01DK54471)
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Chemotherapy-induced organ toxicity mitigation
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- p21, acute kidney injury, renal ischemia-reperfusion injury, cell cycle arrest, proliferating cell nuclear antigen, p21 knockout mice, kidney injury, mortality, mitotic activity
- MeSH terms
- Animals, Gene Expression Regulation, Ischemia, Renal Circulation, Reperfusion Injury, Survival Analysis, Cyclins, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p21, Mice, Acute Kidney Injury
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