Hypoxia induces β cell death by inhibiting the adaptive UPR
(2015) Islet Society and Australian Islet Study Group Joint Annual Meeting — Location: Sydney, Australia (19.July.2015)
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- Abstract
- Aims/hypothesis: Hypoxia is implicated in the loss of functional beta cell mass in type 2 diabetes and with islet transplantation, although the mechanisms are unknown. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum homeostasis and beta cell integrity. Here we investigated the influence of hypoxia on the adaptive UPR and the role it plays in apoptosis. Methods: Mouse islets and MIN6 cells were exposed to various O2 tensions. Gene expression was inhibited using siRNA. JNK was inhibited using SP600125. Islets from db/+ and (pre)diabetic db/db mice were used. mRNA and protein levels were measured by real-time RT-PCR and western blot and apoptosis by DNA fragmentation ELISA. Results: O2 deprivation (1% vs 20%; 4-24h) markedly reduced the mRNA and protein levels of adaptive UPR genes, including Hspa5, Hsp90b1 and Fkbp11 as well as Xbp1 splicing and PERK phosphorylation. Opposite effects were observed in MEF cells suggesting a beta cell specific response. This was accompanied by increased EIF2A phosphorylation and upregulation of integrated stress response (ISR) genes, including Ddit3, Atf3 and Trb3. Interestingly, JNK or Ddit3 inhibition, but not Hif1α inhibition, partially prevented the hypoxia-mediated loss of adaptive UPR gene expression and significantly protected against hypoxia-induced apoptosis. Moreover, Hspa5 overexpression alone partially protected against hypoxia-induced apoptosis. Finally, hypoxia-response genes, including Tpi1, Gapdh and Eno1, were markedly upregulated in vivo in the islets of diabetic db/db mice, but not in prediabetic db/db mice, suggesting that islet hypoxia correlates with beta cell failure and downregulation of adaptive UPR gene expression in diabetic db/db islets. Conclusions/interpretation: Hypoxia inhibits the adaptive UPR in beta cells partially via Ddit3 and JNK activation, but independently of Hif1α. Downregulation of the adaptive UPR contributes to hypoxia-induced beta cell apoptosis and may play a role in the loss of functional beta cell mass in type 2 diabetes.
- Affiliations
Garvan Institute of Medical Research
Citations
Bensellam, M., MAxwell, E., Jonas, J.-C., Chan, J. Y., & Laybutt, D. R. (2015). Hypoxia induces β cell death by inhibiting the adaptive UPR. Islet Society and Australian Islet Study Group Joint Annual Meeting, Sydney, Australia. https://hdl.handle.net/2078.5/93570