Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Am J Transplant. 2021 Sep;21(9):2964-2977. doi: 10.1111/ajt.16561. Epub 2021 Apr 2.
Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity.
钙调神经磷酸酶抑制剂（CNIs）是一种强效的免疫抑制剂，广泛用于实体器官移植后预防排斥反应。尽管有效，但长期使用 CNI 与肾毒性有关。这种不良反应的病因复杂，有效的治疗干预措施仍有待确定。本研究使用体外技术和 CNI 介导的肾毒性小鼠模型，发现 CNI 环孢素 A（CsA）和他克莫司（TAC）具有相似的肾小管上皮细胞损伤机制，包括线粒体功能障碍和高迁移率族蛋白 B1（HMGB1）的释放。CNI 通过线粒体功能障碍和向糖酵解代谢的转变促进能量代谢重编程。这些事件伴随着细胞间黏附力的降低、上皮细胞表型的丧失和 HMGB1 的释放。值得注意的是，Erk1/2 抑制剂可有效减少 HMGB1 的释放，而包含泛半胱天冬酶抑制剂 zVAD-FMK 时也观察到类似的抑制剂。在体内，虽然 CNI 激活组织促重塑信号通路，但 MAPK/Erk1/2 抑制剂可预防肾毒性，包括减少肾上皮细胞 HMGB1 的释放和在尿液中的积累。总之，HMGB1 是 CNI 诱导的进行性肾毒性的早期标志物。我们认为，促重塑信号通路和线粒体氧化还原/能量代谢平衡的丧失是改善 CNI 介导的肾毒性的关键治疗靶点。
