Dynamics of necroptosis in kidney ischemia-reperfusion injury
Necroptosis, a pathway of regulated necrosis, involves recruitment and activation of RIPK1, RIPK3 and MLKL, leading to cell membrane rupture, cell death and release of intracellular contents causing further injury and inflammation. Necroptosis is believed to play an important role in the pathogenesi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251452/full |
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| author | Aspasia Pefanis Aspasia Pefanis Aspasia Pefanis Anjan K. Bongoni Jennifer L. McRae Evelyn J. Salvaris Nella Fisicaro James M. Murphy James M. Murphy James M. Murphy Francesco L. Ierino Francesco L. Ierino Peter J. Cowan Peter J. Cowan |
| author_facet | Aspasia Pefanis Aspasia Pefanis Aspasia Pefanis Anjan K. Bongoni Jennifer L. McRae Evelyn J. Salvaris Nella Fisicaro James M. Murphy James M. Murphy James M. Murphy Francesco L. Ierino Francesco L. Ierino Peter J. Cowan Peter J. Cowan |
| author_sort | Aspasia Pefanis |
| collection | DOAJ |
| description | Necroptosis, a pathway of regulated necrosis, involves recruitment and activation of RIPK1, RIPK3 and MLKL, leading to cell membrane rupture, cell death and release of intracellular contents causing further injury and inflammation. Necroptosis is believed to play an important role in the pathogenesis of kidney ischemia-reperfusion injury (IRI). However, the dynamics of necroptosis in kidney IRI is poorly understood, in part due to difficulties in detecting phosphorylated MLKL (pMLKL), the executioner of the necroptosis pathway. Here, we investigated the temporal and spatial activation of necroptosis in a mouse model of unilateral warm kidney IRI, using a robust method to stain pMLKL. We identified the period 3-12 hrs after reperfusion as a critical phase for the activation of necroptosis in proximal tubular cells. After 12 hrs, the predominant pattern of pMLKL staining shifted from cytoplasmic to membrane, indicating progression to the terminal phase of necroptotic cell death. Mlkl-ko mice exhibited reduced kidney inflammation at 12 hrs and lower serum creatinine and tubular injury at 24 hrs compared to wild-type littermates. Interestingly, we observed increased apoptosis in the injured kidneys of Mlkl-ko mice, suggesting a relationship between necroptosis and apoptosis in kidney IRI. Together, our findings confirm the role of necroptosis and necroinflammation in kidney IRI, and identify the first 3 hrs following reperfusion as a potential window for targeted treatments. |
| first_indexed | 2024-03-11T13:45:13Z |
| format | Article |
| id | doaj.art-635bf00875244241a3684b1d6eecfcef |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T13:45:13Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-635bf00875244241a3684b1d6eecfcef2023-11-02T10:45:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12514521251452Dynamics of necroptosis in kidney ischemia-reperfusion injuryAspasia Pefanis0Aspasia Pefanis1Aspasia Pefanis2Anjan K. Bongoni3Jennifer L. McRae4Evelyn J. Salvaris5Nella Fisicaro6James M. Murphy7James M. Murphy8James M. Murphy9Francesco L. Ierino10Francesco L. Ierino11Peter J. Cowan12Peter J. Cowan13Immunology Research Centre, St Vincent’s Hospital, Melbourne, VIC, AustraliaDepartment of Medicine, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Nephrology, St Vincent’s Hospital, Melbourne, VIC, AustraliaImmunology Research Centre, St Vincent’s Hospital, Melbourne, VIC, AustraliaImmunology Research Centre, St Vincent’s Hospital, Melbourne, VIC, AustraliaImmunology Research Centre, St Vincent’s Hospital, Melbourne, VIC, AustraliaImmunology Research Centre, St Vincent’s Hospital, Melbourne, VIC, AustraliaWalter and Eliza Hall Institute of Medical Research, Parkville, VIC, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, VIC, AustraliaDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, AustraliaDepartment of Medicine, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Nephrology, St Vincent’s Hospital, Melbourne, VIC, AustraliaImmunology Research Centre, St Vincent’s Hospital, Melbourne, VIC, AustraliaDepartment of Medicine, The University of Melbourne, Melbourne, VIC, AustraliaNecroptosis, a pathway of regulated necrosis, involves recruitment and activation of RIPK1, RIPK3 and MLKL, leading to cell membrane rupture, cell death and release of intracellular contents causing further injury and inflammation. Necroptosis is believed to play an important role in the pathogenesis of kidney ischemia-reperfusion injury (IRI). However, the dynamics of necroptosis in kidney IRI is poorly understood, in part due to difficulties in detecting phosphorylated MLKL (pMLKL), the executioner of the necroptosis pathway. Here, we investigated the temporal and spatial activation of necroptosis in a mouse model of unilateral warm kidney IRI, using a robust method to stain pMLKL. We identified the period 3-12 hrs after reperfusion as a critical phase for the activation of necroptosis in proximal tubular cells. After 12 hrs, the predominant pattern of pMLKL staining shifted from cytoplasmic to membrane, indicating progression to the terminal phase of necroptotic cell death. Mlkl-ko mice exhibited reduced kidney inflammation at 12 hrs and lower serum creatinine and tubular injury at 24 hrs compared to wild-type littermates. Interestingly, we observed increased apoptosis in the injured kidneys of Mlkl-ko mice, suggesting a relationship between necroptosis and apoptosis in kidney IRI. Together, our findings confirm the role of necroptosis and necroinflammation in kidney IRI, and identify the first 3 hrs following reperfusion as a potential window for targeted treatments.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251452/fullnecroptosisischemia-reperfusionnecroinflammationmlklacute kidney injurychronic kidney disease |
| spellingShingle | Aspasia Pefanis Aspasia Pefanis Aspasia Pefanis Anjan K. Bongoni Jennifer L. McRae Evelyn J. Salvaris Nella Fisicaro James M. Murphy James M. Murphy James M. Murphy Francesco L. Ierino Francesco L. Ierino Peter J. Cowan Peter J. Cowan Dynamics of necroptosis in kidney ischemia-reperfusion injury Frontiers in Immunology necroptosis ischemia-reperfusion necroinflammation mlkl acute kidney injury chronic kidney disease |
| title | Dynamics of necroptosis in kidney ischemia-reperfusion injury |
| title_full | Dynamics of necroptosis in kidney ischemia-reperfusion injury |
| title_fullStr | Dynamics of necroptosis in kidney ischemia-reperfusion injury |
| title_full_unstemmed | Dynamics of necroptosis in kidney ischemia-reperfusion injury |
| title_short | Dynamics of necroptosis in kidney ischemia-reperfusion injury |
| title_sort | dynamics of necroptosis in kidney ischemia reperfusion injury |
| topic | necroptosis ischemia-reperfusion necroinflammation mlkl acute kidney injury chronic kidney disease |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251452/full |
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