In vivo siRNA delivery of Keap1 modulates death and survival signaling pathways and attenuates concanavalin-A-induced acute liver injury in mice
Publisher
The Company of BiologistsDate
2014-01-01Citation
10.1242/dmm.015537
Disease Models & Mechanisms 7.9 (2014): 1093-1100
ISSN
1754-8403 (print); 1754-8411 (online)DOI
10.1242/dmm.015537Funded by
This work was supported by SAF2012-33283 (Ministerio de Economía y Competitividad, Spain), Comunidad de Madrid S2010/BMD-2423 and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Instituto de Salud Carlos III, Spain)Project
Comunidad de Madrid. S2010/BMD-2423/MOIREditor's Version
http://dx.doi.org/10.1242/dmm.015537Subjects
Acute liver failure; Apoptosis; In vivo siRNA; Keap1; Nrf2; MedicinaRights
© 2014 the authorsAbstract
Oxidative stress contributes to the progression of acute liver failure
(ALF). Transcription factor nuclear factor-erythroid 2-related factor
(Nrf2) serves as an endogenous regulator by which cells combat
oxidative stress. We have investigated liver damage and the balance
between death and survival signaling pathways in concanavalin A
(ConA)-mediated ALF using in vivo siRNA delivery targeting Keap1
in hepatocytes. For that goal, mice were injected with Keap1- or
luciferase-siRNA-containing liposomes via the tail vein. After
48 hours, ALF was induced by ConA. Liver histology, proinflammatory
mediators, antioxidant responses, cellular death, and
stress and survival signaling were assessed. Keap1 mRNA and
protein levels significantly decreased in livers of Keap1-siRNAinjected
mice. In these animals, histological liver damage was less
evident than in control mice when challenged with ConA. Likewise,
markers of cellular death (FasL and caspases 8, 3 and 1) decreased
at 4 and 8 hours post-injection. Nuclear Nrf2 and its target,
hemoxygenase 1 (HO1), were elevated in Keap1-siRNA-injected mice
compared with control animals, resulting in reduced oxidative stress
in the liver. Similarly, mRNA levels of pro-inflammatory cytokines were
reduced in livers from Keap1-siRNA-injected mice. At the molecular
level, activation of c-jun (NH2) terminal kinase (JNK) was ameliorated,
whereas the insulin-like growth factor I receptor (IGFIR) survival
pathway was maintained upon ConA injection in Keap1-siRNA-treated
mice. In conclusion, our results have revealed a potential therapeutic
use of in vivo siRNA technology targeted to Keap1 to combat
oxidative stress by modulating Nrf2-mediated antioxidant responses
and IGFIR survival signaling during the progression of ALF
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Google Scholar:González-Rodríguez, Agueda
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Reibert, Bjorn
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Amann, Thomas
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Constien, Rainier
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Rondinone, Cristina M.
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Valverde, Ángela M.
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