期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 16, 页码 4182-4187出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716578115
关键词
AKI; cell death; RIPK1; TWEAK; Fn14
资金
- Fondo de Investigacion Sanitaria Grant [PI15/00298, CP12/03262, CP14/00133, PI17/01495, PI14/00386, PI16/02057, PI16/01900]
- Research Institute Carlos III (ISCIII)-Networks for Cooperative Research in Health, Red de Investigacion Renal Grant [RD016/0009]
- Fondo Europeo de Desarrollo Regional
- Sociedad Espanola de Nefrologia
- Fundacion Renal Inigo Alvarez de Toledo
- Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas
- ISCIII Miguel Servet
- Fundacion Conchita Rabago
- Consejeria de Educacion, Juventud y Deporte Comunidad de Madrid/FSE
- Heisenberg Professorship Program of the German Research Foundation
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 receptorinteracting protein kinase 1 (RIPK1), RIPK3, and mixed lineage domainlike 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.
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