当前，在实体器官移植中西罗莫司（雷帕霉素）被用于诱导和维持期免疫抑制治疗，包括应用于胰腺移植、肾移植和胰岛移植。西罗莫司被认为可能对于胰岛β细胞和肾功能有损害作用。我们研究了西罗莫司对于胰岛细胞、足细胞及肾小管细胞活力的影响。西罗莫司在体外能够降低胰岛细胞和HK-2人肾小管周细胞的活性。该毒副作用和胰岛细胞血管内皮生长因子（VEGF）释放下降相关，但与管周细胞无关。西罗莫司能够减少鼠β细胞的活性和VEGF的产生，且阻断VEGF-164与其活性下降相关。鼠胰岛细胞转染腺病毒VEGF-165能够提高胰岛细胞的活性。这些数据与先前的假设一致，西罗莫司通过阻断VEGF介导的生存途径对于胰岛细胞和β细胞产生毒性。

Presently, sirolimus (rapamycin) is used as both induction and maintenance immunosuppression in solid organ transplants, including whole pancreas and kidney, and islet transplantation. Sirolimus has been suggested to have deleterious effects on islet beta-cell and renal function. We investigated the effect of sirolimus on the viability of islets, podocytes, and renal tubular cells. Sirolimus reduced the viability of islets and HK-2 human proximal renal tubular cells in vitro. This toxic effect was associated with a reduction of vascular endothelial growth factor (VEGF) release by islets but not the proximal tubular cells. Sirolimus reduced both viability and VEGF production by murine beta-cells, and blockade of VEGF-164 was associated with a reduction in viability. Transfection of murine islets with adenoviral VEGF-165 improved islet viability. These data are consistent with the hypothesis that sirolimus is toxic to islets and beta-cells by blockade of VEGF-mediated survival pathways.

[责任编辑:唐雷 ]