Deletion of ARNT (Aryl hydrocarbon receptor nuclear translocator) in beta-cells causes islet transplant failure with impaired beta-cell function
BACKGROUND: Replacing beta-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of beta-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates beta-cell function, and potentially survival. Lack of ARNT impairs the ability of beta-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown. AIM: To investigate the effect of beta-cell deletion of ARNT on graft outcomes. METHODS: Islets were isolated from donor mice which had beta-cell specific ARNT-deletion (beta-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) (1/2) of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas. RESULTS: In the supra-physiological-mass model (3:1), both groups achieved reasonable glycaemia, with slightly higher levels in beta-ARNT-recipients. In adequate-mass model (1:1), beta-ARNT recipients had poor glucose control versus floxed-control recipients and versus the beta-ARNT donors. In the low-beta-cell-mass model ((1/2):1) beta-ARNT transplants completely failed, whereas controls had good outcomes. Unexpectedly, there was no difference in the graft insulin content or beta-cell mass between groups indicating that the defect was not due to early altered beta-cell survival. CONCLUSION: Outcomes for islet transplants lacking beta-cell ARNT were poor, unless markedly supra-physiological masses of islets were transplanted. In the 1:1 transplant model, there was no difference in beta-cell volume. This is surprising because transplants of islets lacking one of the ARNT-partners HIF-1alpha have increased apoptosis and decreased islet volume. ARNT also partners HIF-2alpha and AhR (aryl hydrocarbon receptor) to form active transcriptional complexes, and further work to understand the roles of HIF-2alpha and AhR in transplant outcomes is needed.
|ISBN||1932-6203 (Electronic) 1932-6203 (Linking)|
|Authors||Lalwani, A.; Stokes, R. A.; Lau, S. M.; Gunton, J. E.;|
|Responsible Garvan Author|
|Publisher Name||PLoS ONE|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24878748|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/download.php?12370_12747/pone.0098435.pdf|