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Decoding cold ischaemia time impact on kidney graft: the kinetics of the unfolded protein response pathways.
Le Pape, Sylvain; Pasini-Chabot, Ophélie; Couturier, Pierre; Delpech, Pierre-Olivier; Volmer, Romain; Quellard, Nathalie; Ploeg, Rutger; Hauet, Thierry; Thuillier, Raphaël.
Afiliação
  • Le Pape S; a Inserm, U1082 IRTOMIT Poitiers , France.
  • Pasini-Chabot O; b Faculté de Médecine et de Pharmacie , Université de Poitiers , Poitiers , France.
  • Couturier P; a Inserm, U1082 IRTOMIT Poitiers , France.
  • Delpech PO; c CHU Poitiers, Service de Biochimie , Pôle BIOSPHARM , Poitiers , France.
  • Volmer R; c CHU Poitiers, Service de Biochimie , Pôle BIOSPHARM , Poitiers , France.
  • Quellard N; a Inserm, U1082 IRTOMIT Poitiers , France.
  • Ploeg R; d CHU Poitiers, Service d'Urologie , Pôle DUNE , Poitiers , France.
  • Hauet T; e University of Cambridge Metabolic Research Laboratories and National Institute for Health Research , Cambridge , UK.
  • Thuillier R; f CHU de Poitiers, Dept d'Anatomo-pathologie, Pôle BIOSPHARM , Poitiers , France.
Artif Cells Nanomed Biotechnol ; 46(sup3): S873-S885, 2018.
Article em En | MEDLINE | ID: mdl-30280609
The relationship between cold ischaemia time (CIT) and adverse outcome is now acknowledged. However, the underlying mechanisms remain to be defined, which slows the development of adapted therapeutics and diagnostics. We explored the impact of CIT in both preclinical and in vitro models of preservation. We determined that the endoplasmic reticulum (ER) and its stress response (unfolded protein response, UPR) were regulated in close association with CIT; the eIF2α-ATF4 pathway was inhibited early (1-8 h) at the detriment of cell survival, while the ATF6 pathway was activated late (12-24 h) and associated with cell death. The IRE1α-XBP1 branch was activated at reperfusion only if CIT extended beyond 8 h, and had a dual role on cell fate - deleterious through IRE1's RNase activity and beneficial through IRE1α other roles. Finally, the pro-apoptotic factor CHOP was a common target of both ATF6 and IRE1α pathways and was associated with elongated CIT and increased cell death. Microarray analysis of human transplanted kidney confirmed that UPR markers were regulated by CIT and that CHOP was associated with adverse outcome. We show that UPR could be a critical pathway explaining the relationship between CIT and graft outcome, highlighting the potential for UPR-based therapeutics and diagnostics to improve transplantation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Transplante de Rim / Isquemia Fria / Resposta a Proteínas não Dobradas / Rim Tipo de estudo: Guideline / Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Transplante de Rim / Isquemia Fria / Resposta a Proteínas não Dobradas / Rim Tipo de estudo: Guideline / Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article