Regulated necrosis in kidney ischemia-reperfusion injury
Open accessAbstract
Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality, and adverse outcomes in transplantation. Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. This regulated necrosis (RN) takes several forms, with necroptosis and ferroptosis being the best described. The precise mechanisms and relationships between the RN pathways in renal IRI are currently the subject of active research. The common endpoint of RN is cell membrane rupture, resulting in the release of cytosolic components with subsequent inflammation and activation of the immune system. We review the evidence and mechanisms of RN in the kidney following renal IRI, and discuss the use of small molecule inhibitors and genetically modified mice to better understand this process and guide potentially novel therapeutic interventions.
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Rapid reperfusion during the reperfusion phase leads to oxidative stress, mitochondrial dysfunction, and cell death, thereby impairing renal function.
“rapid reperfusion during the reperfusion phase leads to oxidative stress, mitochondrial dysfunction, and cell death, thereby impairing renal function”
From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Pefanis et al., 2019
The S3 segment of the proximal tubule is the most consistently injured region in renal I/R injury because of its high oxidative metabolism, low glycolytic reserve, and dependence on Na+/K+-ATPase under conditions of borderline O2 supply.
“The S3 segment of the proximal tubule, located in the outer stripe of the outer medulla, is the most consistently injured region because of its high oxidative metabolism, low glycolytic reserve and dependence on Na+/K+-ATPase under conditions of borderline O2 supply”
From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Pefanis et al., 2019
During the ischemic phase, cessation of oxygen and nutrient supply significantly impairs renal metabolism.
“During the ischemic phase, the cessation of oxygen and nutrient supply significantly impairs renal metabolism”
From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Pefanis et al., 2019
Upon reperfusion, abrupt reoxygenation triggers a burst of mitochondrial superoxide production and a transient increase in tissue ROS.
“Upon reperfusion, abrupt reoxygenation triggers a burst of mitochondrial superoxide production and a transient increase in tissue ROS”
From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Pefanis et al., 2019
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- Authors
- Pefanis, A., Ierino, F. L., Murphy, J. M., & Cowan, P. J.
- Affiliations
- The University of Melbourne (AU)
- Corresponding author
- Cowan, Peter J.
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 96
- Issue
- 2
- Pages
- 291-301
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W2921397389
- Cited by
- 361
- References
- 15
- Citations by year
- 2026: 50 · 2025: 69 · 2024: 67 · 2023: 60 · 2022: 56 · 2021: 26 · 2020: 27 · 2019: 6
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- regulated necrosis, ischemia-reperfusion injury, acute kidney injury, necroptosis, ferroptosis, tubular cell death, apoptosis, cell membrane rupture, inflammation, kidney transplantation, small molecule inhibitors, genetically modified mice
- MeSH terms
- Necroptosis, Ferroptosis, Animals, Disease Models, Animal, Epithelial Cells, Humans, Kidney Failure, Chronic, Kidney Tubules, Mice, Transgenic, Necrosis, Oxazepines, Protein Kinases, Regional Blood Flow, Triazoles, Signal Transduction, Reperfusion Injury, Kidney Transplantation, Randomized Controlled Trials as Topic, Treatment Outcome, Apoptosis, Clinical Trials, Phase II as Topic, Protein Kinase Inhibitors, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Microvessels, Acute Kidney Injury
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