Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari 'A. Moro', Italy.
Am J Transplant. 2011 Aug;11(8):1656-64. doi: 10.1111/j.1600-6143.2011.03590.x. Epub 2011 Jun 14.
Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Because Klotho is an aging-suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin-induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser(473) expression directly correlating with long-term rapamycin exposure, FE(PO4) and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation.
雷帕霉素是一种免疫抑制剂，用于预防肾移植后的排斥反应，它影响磷酸盐稳态，诱导胰岛素抵抗，并已被证明能延长动物模型的寿命。因为 Klotho 是一个控制磷酸盐代谢和胰岛素敏感性的衰老抑制基因，我们研究了雷帕霉素对 Klotho 表达的影响。共纳入 100 例肾移植受者，其中 50 例接受雷帕霉素慢性治疗，50 例接受钙调神经磷酸酶抑制剂治疗；20 例健康受试者作为对照。雷帕霉素组血清磷酸盐低于钙调神经磷酸酶抑制剂组，磷酸盐排泄增加，重吸收减少。此外，雷帕霉素还增加了胰岛素抵抗，表现为 HOMA 指数升高。雷帕霉素处理永生化的近端肾小管细胞系诱导 Klotho 的表达，AKT 在 Ser473 处的磷酸化，mTORC2 的下游靶点和 RICTOR，mTORC2 的主要成分的表达。AKT 抑制减少了雷帕霉素诱导的 Klotho 表达。体内雷帕霉素治疗诱导更高程度的 RICTOR 和 AKT Ser(473)表达，与长期雷帕霉素暴露、FE(PO4)和 HOMA 指数直接相关。总之，我们的数据表明，雷帕霉素可能通过 mTORC2 激活影响磷酸盐稳态和胰岛素抵抗，调节 Klotho 表达。
