Islet Graft Response to Transplantation Injury Includes Upregulation of Protective as Well as Apoptotic Genes

Pancreatic islets are particularly vulnerable in the initial days after transplantation when multiple factors converge to damage the islet graft. The aim of this study was to investigate the expression profile of genes involved in damage and protection of β-cells in the initial days after syngeneic islet transplantation. We studied the expression of a set of selected genes involved in apoptosis (Bcl2, Bclx_L, Bax, Bad, Bid, and CHOP), cytokine defense, (SOCS-1 and SOCS-3), or free radical protection (Hmox1, Cu/Zn-SOD, Mn-SOD, and Hsp70). Because hyperglycemia has deleterious effects on islet transplantation outcome, we studied its effect on the expression of these genes. Five hundred islets were syngeneically transplanted under the kidney capsule of normoglycemic or streptozotocin-induced diabetic Lewis rats. Gene expression was analyzed by quantitative real-time RT-PCR in grafts 1, 3, and 7 days after transplantation, and in freshly isolated islets. The expression of proapoptotic genes Bid and CHOP, as well as protective genes Bclx_L, Socs1, Socs3, Hmox1, and MnSod, was maximally increased 1 day after transplantation, and in most cases it remained increased 7 days later, indicating the presence of a protective response against cell damage. In contrast, the expression of Bcl2, Bax, Bad, Cu/ZnSod, and Hsp70 genes did not change. Hyperglycemia did not modify the expression of most studied genes. However, MnSod and Ins2 expression was increased and reduced, respectively, on day 7 after transplantation to diabetic recipients, suggesting that hyperglycemia increased oxidative stress and deteriorated β-cell function in transplanted islets.