The University of Melbourne Department of Surgery, Austin Health, Studley Rd., Heidelberg, VIC, 3084, Australia.
Department of Urology, Austin Health, Heidelberg, VIC, Australia.
Biometals. 2018 Oct;31(5):821-834. doi: 10.1007/s10534-018-0125-3. Epub 2018 Jul 4.
Ischaemia-reperfusion injury (IRI) during various surgical procedures, including partial nephrectomy for kidney cancer or renal transplantation, is a major cause of acute kidney injury and chronic kidney disease. Currently there are no drugs or methods for protecting human organs, including the kidneys, against the peril of IRI. The aim of this study was therefore to investigate the reno-protective effect of Zn preconditioning in a clinically relevant large animal sheep model of IRI. Further the reno-protective effectiveness of Zn preconditioning was tested on normal human kidney cell lines HK-2 and HEK293. Anaesthetised sheep were subjected to uninephrectomy and 60 min of renal ischaemia followed by reperfusion. Sheep were preconditioned with intravenous injection of zinc chloride prior to occlusion. Serum creatinine and urea were measured before ischaemia and for 7 days after reperfusion. HK-2 and HEK293 cells were subjected to in vitro IRI using the oxygen- and glucose-deprivation model. Zn preconditioning reduced ischaemic burden determined by creatinine and urea rise over time by ~ 70% in sheep. Zn preconditioning also increased the survival of normal human kidney cells subjected to cellular stress such as hypoxia, hydrogen peroxide injury, and serum starvation. Overall, our protocol incorporating specific Zn dosage, number of dosages (two), time of injection (24 and 4 h prior), mode of Zn delivery (IV) and testing of efficacy in a rat model, a large preclinical sheep model of IRI and cells of human origin has laid the foundation for assessment of the benefit of Zn preconditioning for human applications.
在各种外科手术中，包括部分肾切除术治疗肾癌或肾移植术，都会发生缺血再灌注损伤（IRI），这是急性肾损伤和慢性肾脏病的主要原因。目前，还没有药物或方法可以保护包括肾脏在内的人体器官免受 IRI 的危害。因此，本研究旨在探讨 Zn 预处理在临床相关的大动物绵羊 IRI 模型中的肾脏保护作用。此外，还在正常的人肾细胞系 HK-2 和 HEK293 上测试了 Zn 预处理的肾脏保护效果。麻醉绵羊进行单侧肾切除术和 60 分钟的肾缺血，随后进行再灌注。在闭塞前，绵羊通过静脉注射氯化锌进行预处理。在缺血前和再灌注后 7 天测量血清肌酐和尿素。HK-2 和 HEK293 细胞通过缺氧和葡萄糖剥夺模型进行体外 IRI。Zn 预处理可将绵羊的缺血负担通过肌酐和尿素的升高来衡量，时间上降低了约 70%。Zn 预处理还增加了正常人类肾脏细胞在缺氧、过氧化氢损伤和血清饥饿等细胞应激下的存活率。总的来说，我们的方案包括特定的 Zn 剂量、剂量次数（2 次）、注射时间（再灌注前 24 小时和 4 小时）、Zn 给药方式（IV）和在大鼠模型、大的临床前绵羊 IRI 模型和人类来源的细胞中测试功效，为评估 Zn 预处理对人类应用的益处奠定了基础。
