Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background: The Unfolded Protein Response (UPR) is activated as an adaptive response to endoplasmic reticulum (ER) stress, however if ER stress is not resolved, UPR dependent pathways lead to apoptosis. UPR activation has been implicated in beta cell dysfunction and apoptosis. We investigated the effect of hypoxia on ER stress pathways in isolated human islets and expression of ER stress markers in human donor pancreases following ischemic injury.
Methods: Human islet preparations from normoglycaemic donors were exposed to hypoxic conditions and RNA was extracted at baseline and immediately post hypoxia exposure. Islets were pre-treated with Rapamycin prior to hypoxic exposure and analysis of UPR mediators performed by qPolymerase Chain Reaction. Donor pancreases retrieved for transplantation but subsequently declined for implantation and non-ischaemic controls were also assessed for evidence of ER stress. Immunofluorescent staining for UPR markers and apoptosis (TUNEL), were co-stained with insulin to identify beta cells in formalin-fixed paraffin embedded pancreas sections.
Results: Hypoxia resulted in significant upregulation of 2 mediators of the UPR; Binding Immunoglobulin Protein (BIP) and pro-apoptotic C/EBP Homologous Protein (CHOP) mRNA expression (p=0.03, 0.0007 respectively). Pre-treatment with Rapamycin significantly abrogated this effect in a dose-dependent fashion. Individual islet preparations varied in the extent of hypoxia-induced stress. The donor pancreas also exhibited markers of ER stress, compared to non-ischaemic controls.
Conclusion: Activation of ER stress pathways secondary to islet hypoxia may be implicated in beta cell apoptosis and loss post-transplantation. Modification of the UPR may be initiated using direct therapy of islet preparations or the donor pancreas prior to implantation, to improve beta cell survival and functionality.
CITATION INFORMATION: Sandhu B., Prendecki M., Vallant N., Rutter G., Pusey C., Papalois V. Hypoxia Results in Endoplasmic Reticulum Stress and Activation of the Unfolded Protein Response in Isolated Human Islets and Human Donor Pancreases Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Sandhu B, Prendecki M, Vallant N, Rutter G, Pusey C, Papalois V. Hypoxia Results in Endoplasmic Reticulum Stress and Activation of the Unfolded Protein Response in Isolated Human Islets and Human Donor Pancreases [abstract]. https://atcmeetingabstracts.com/abstract/hypoxia-results-in-endoplasmic-reticulum-stress-and-activation-of-the-unfolded-protein-response-in-isolated-human-islets-and-human-donor-pancreases/. Accessed July 24, 2021.
« Back to 2018 American Transplant Congress