The Clinical Research, Investigation and Systems Modeling of Acute illness Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Nephrol Dial Transplant. 2012 Aug;27(8):3100-9. doi: 10.1093/ndt/gfr766. Epub 2012 Jan 31.
In most patients, acute kidney injury (AKI) represents the combined effects of ischemic, toxic and inflammatory insults. No effective pharmacologic interventions have been developed to prevent AKI or to improve outcomes to date. Cyclosporine A (CsA) is a calcineurin inhibitor that mediates T-cell receptor signaling, suppresses inflammatory cytokine expression and inhibits leukocyte migration. It is also a potent inhibitor of mitochondrial permeability, protecting cells from death. These properties make it a potentially valuable drug to prevent or treat AKI. It does, however, carry a significant risk of nephrotoxicity, especially with chronic use. By contrast, a single dose of CsA may be protective while limiting the risk of nephrotoxicity.
We conducted a controlled animal experiment in male CD-1 mice. Specifically, mice were subjected to folic acid (FA)-induced AKI and then randomly assigned to sham operation or one of three dosage of CsA treatment groups. Results Intraperitoneal injection of FA consistently induced AKI. Serum interleukin (IL)-6 and urinary neutrophil gelatinase-associated lipocalin (NGAL) rose 1 day after FA injection. Compared to sham treatment, one dose (1 and 5 mg/kg body weight) of CsA significantly reduced kidney tubular cell apoptosis, serum creatinine, blood urea, serum IL-6 and urinary NGAL 2 days after FA injection. It was also shown to block the inflammatory mediator tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) expression, nuclear factor kappa-B (NFκB) activation, inflammatory cell infiltration and interstitial fibrosis 14 days after treatment in a dose-dependent fashion. By contrast, a dose of 10 mg/kg body weight CsA resulted in nephrotoxicity in the setting of FA-induced AKI.
A single dose of CsA, currently used for organ transplant, significantly protects mice from FA-induced AKI, presumably through inhibition of cell death, inflammatory reaction, interstitial cell infiltration and fibrosis. The protective effects have the potential to open a completely new line of investigation in the prevention and treatment of AKI.
在大多数患者中，急性肾损伤（AKI）代表缺血、毒性和炎症损伤的综合作用。迄今为止，尚未开发出有效的药物干预措施来预防 AKI 或改善预后。环孢素 A（CsA）是一种钙调神经磷酸酶抑制剂，可介导 T 细胞受体信号转导，抑制炎症细胞因子的表达，并抑制白细胞迁移。它也是线粒体通透性的有效抑制剂，可防止细胞死亡。这些特性使其成为预防或治疗 AKI 的潜在有价值的药物。然而，它确实存在严重的肾毒性风险，尤其是在长期使用时。相比之下，单次 CsA 剂量可能具有保护作用，同时限制肾毒性的风险。
我们在雄性 CD-1 小鼠中进行了一项对照动物实验。具体来说，将小鼠进行叶酸（FA）诱导的 AKI 处理，然后随机分配至假手术或三种 CsA 剂量治疗组之一。结果 FA 注射后 1 天，血清白细胞介素（IL）-6 和尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL）升高。与假手术处理相比，1 剂量（1 和 5 mg/kg 体重）的 CsA 显著降低了 FA 注射后 2 天的肾小管细胞凋亡、血清肌酐、血尿素、血清 IL-6 和尿 NGAL。它还显示出以剂量依赖的方式阻断炎症介质肿瘤坏死因子（TNF）样凋亡弱诱导剂（TWEAK）表达、核因子 kappa-B（NFκB）激活、炎症细胞浸润和间质纤维化，在治疗后 14 天。相比之下，在 FA 诱导的 AKI 中，10 mg/kg 体重的 CsA 剂量导致肾毒性。
目前用于器官移植的单次 CsA 剂量可显著保护小鼠免受 FA 诱导的 AKI，可能通过抑制细胞死亡、炎症反应、间质细胞浸润和纤维化。这些保护作用有可能为 AKI 的预防和治疗开辟全新的研究途径。
