TWEAK and RIPK1 mediate a second wave of cell death during AKI
| Autor: | Susana Carrasco, Maria Dolores Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz, Jesús Egido, Anne von Mässenhausen, Ana Belen Sanz, Pablo Cannata-Ortiz, Diego Martin-Sanchez, Andreas Linkermann, Miguel Fontecha-Barriuso |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Indoles Necroptosis Apoptosis Inflammation Corrections Cell Line Proinflammatory cytokine Kidney Tubules Proximal Mice Necrosis 03 medical and health sciences RIPK1 Folic Acid medicine Animals Caspase Cytokine TWEAK Multidisciplinary biology business.industry Imidazoles Acute kidney injury Acute Kidney Injury medicine.disease Enzyme Activation Mice Inbred C57BL 030104 developmental biology Cellular Microenvironment TWEAK Receptor Receptor-Interacting Protein Serine-Threonine Kinases Cancer research biology.protein Female medicine.symptom business |
| Zdroj: | Proceedings of the National Academy of Sciences. 115:4182-4187 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Acute kidney injury (AKI) is characterized by necrotic tubular cell death and inflammation. The TWEAK/Fn14 axis is a mediator of renal injury. Diverse pathways of regulated necrosis have recently been reported to contribute to AKI, but there are ongoing discussions on the timing or molecular regulators involved. We have now explored the cell death pathways induced by TWEAK/Fn14 activation and their relevance during AKI. In cultured tubular cells, the inflammatory cytokine TWEAK induces apoptosis in a proinflammatory environment. The default inhibitor of necroptosis [necrostatin-1 (Nec-1)] was protective, while caspase inhibition switched cell death to necroptosis. Additionally, folic acid-induced AKI in mice resulted in increased expression of Fn14 and necroptosis mediators, such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage domain-like protein (MLKL). Targeting necroptosis with Nec-1 or by genetic RIPK3 deficiency and genetic Fn14 ablation failed to be protective at early time points (48 h). However, a persistently high cell death rate and kidney dysfunction (72-96 h) were dependent on an intact TWEAK/Fn14 axis driving necroptosis. This was prevented by Nec-1, or MLKL, or RIPK3 deficiency and by Nec-1 stable (Nec-1s) administered before or after induction of AKI. These data suggest that initial kidney damage and cell death are amplified through recruitment of inflammation-dependent necroptosis, opening a therapeutic window to treat AKI once it is established. This may be relevant for clinical AKI, since using current diagnostic criteria, severe injury had already led to loss of renal function at diagnosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|