Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury
Abstract The cytosolic protein rubicon (RUBCN) has been implicated in the removal of necrotic debris and autoimmunity. However, the role of RUBCN in models of acute kidney injury (AKI), a condition that typically involves necrotic kidney tubules, was not investigated. Here, we demonstrate that RUBCN...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-03-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04682-3 |
| _version_ | 1818319415310024704 |
|---|---|
| author | Wulf Tonnus Sophie Locke Claudia Meyer Francesca Maremonti Lena Eggert Anne von Mässenhausen Stefan R. Bornstein Douglas R. Green Andreas Linkermann |
| author_facet | Wulf Tonnus Sophie Locke Claudia Meyer Francesca Maremonti Lena Eggert Anne von Mässenhausen Stefan R. Bornstein Douglas R. Green Andreas Linkermann |
| author_sort | Wulf Tonnus |
| collection | DOAJ |
| description | Abstract The cytosolic protein rubicon (RUBCN) has been implicated in the removal of necrotic debris and autoimmunity. However, the role of RUBCN in models of acute kidney injury (AKI), a condition that typically involves necrotic kidney tubules, was not investigated. Here, we demonstrate that RUBCN-deficient mice are hypersensitive to renal damage induced by ischemia-reperfusion injury (IRI) and cisplatin-induced AKI. Combined deficiency of RUBCN and mixed lineage kinase domain-like (MLKL) partially reversed the sensitivity in the IRI model suggesting that the absence of RUBCN sensitizes to necroptosis in that model. Necroptosis is known to contribute to TNFα-induced severe inflammatory response syndrome (SIRS), but we detected no statistically significant difference in overall survival following injection of TNFα in RUBCN-deficient mice. We additionally generated RUBCN-deficient mice which lack gasdermin D (GSDMD), the terminal mediator of pyroptosis, but no reversal of the AKI phenotype was observed. Finally, and in contrast to the previous understanding of the role of RUBCN, we did not find a significant autoimmune phenotype in RUBCN-deficient mice, but detected chronic kidney injury (CKD) in aged RUBCN-deficient mice of both sexes. In summary, our data indicate that RUBCN-deficient mice are hypersensitive to kidney injury. |
| first_indexed | 2024-12-13T10:08:45Z |
| format | Article |
| id | doaj.art-e5aa39e802b1426184909657e90e24bb |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-13T10:08:45Z |
| publishDate | 2022-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e5aa39e802b1426184909657e90e24bb2022-12-21T23:51:30ZengNature Publishing GroupCell Death and Disease2041-48892022-03-011331910.1038/s41419-022-04682-3Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injuryWulf Tonnus0Sophie Locke1Claudia Meyer2Francesca Maremonti3Lena Eggert4Anne von Mässenhausen5Stefan R. Bornstein6Douglas R. Green7Andreas Linkermann8Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Immunology, St. Jude Childrens Research HospitalDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenAbstract The cytosolic protein rubicon (RUBCN) has been implicated in the removal of necrotic debris and autoimmunity. However, the role of RUBCN in models of acute kidney injury (AKI), a condition that typically involves necrotic kidney tubules, was not investigated. Here, we demonstrate that RUBCN-deficient mice are hypersensitive to renal damage induced by ischemia-reperfusion injury (IRI) and cisplatin-induced AKI. Combined deficiency of RUBCN and mixed lineage kinase domain-like (MLKL) partially reversed the sensitivity in the IRI model suggesting that the absence of RUBCN sensitizes to necroptosis in that model. Necroptosis is known to contribute to TNFα-induced severe inflammatory response syndrome (SIRS), but we detected no statistically significant difference in overall survival following injection of TNFα in RUBCN-deficient mice. We additionally generated RUBCN-deficient mice which lack gasdermin D (GSDMD), the terminal mediator of pyroptosis, but no reversal of the AKI phenotype was observed. Finally, and in contrast to the previous understanding of the role of RUBCN, we did not find a significant autoimmune phenotype in RUBCN-deficient mice, but detected chronic kidney injury (CKD) in aged RUBCN-deficient mice of both sexes. In summary, our data indicate that RUBCN-deficient mice are hypersensitive to kidney injury.https://doi.org/10.1038/s41419-022-04682-3 |
| spellingShingle | Wulf Tonnus Sophie Locke Claudia Meyer Francesca Maremonti Lena Eggert Anne von Mässenhausen Stefan R. Bornstein Douglas R. Green Andreas Linkermann Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury Cell Death and Disease |
| title | Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury |
| title_full | Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury |
| title_fullStr | Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury |
| title_full_unstemmed | Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury |
| title_short | Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury |
| title_sort | rubicon deficiency sensitizes mice to mixed lineage kinase domain like mlkl mediated kidney ischemia reperfusion injury |
| url | https://doi.org/10.1038/s41419-022-04682-3 |
| work_keys_str_mv | AT wulftonnus rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT sophielocke rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT claudiameyer rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT francescamaremonti rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT lenaeggert rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT annevonmassenhausen rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT stefanrbornstein rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT douglasrgreen rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury AT andreaslinkermann rubicondeficiencysensitizesmicetomixedlineagekinasedomainlikemlklmediatedkidneyischemiareperfusioninjury |