我们研究了在由出血和主动脉闭塞引起的严重肾缺血再灌注损伤（IRI）的临床相关猪模型中，急性给予卡格列净减轻急性肾损伤（AKI）和减少有害促炎细胞因子释放的潜力。长期卡格列净使用可减轻糖尿病和心力衰竭患者的肾功能衰退并减少 AKI。虽然一些报告表明预防性 SGLT2 抑制可预防 IRI 中的 AKI，但急性给药对 IRI 和炎症的功效尚不清楚。雌性猪 (n=16) 进行 25% 血容量的控制性出血，然后在肾口水平（通过主动脉复苏性血管内球囊闭塞）。主动脉闭塞 5 分钟后，给予单剂量 300 毫克口服卡格列净或载体（生理盐水）。血流动力学监测、肾功能标志物（血清肌酐、血尿素氮、蛋白尿和尿中性粒细胞明胶酶相关脂质运载蛋白）和血清细胞因子浓度（包括白细胞介素：IL-1RA、IL-6、IL-8、IL-10、IL- IRI 后和 6 小时重症监护阶段对肿瘤坏死因子 α）进行了分析。与对照组相比，接受卡格列净的动物 AKI 较轻，肌酐清除率改善，蛋白尿减少，肾小管损伤显着降低，如组织病理学和尿NGAL。此外，促炎细胞因子 IL-6 显着减弱，但抗炎细胞因子（IL-1RA 和 IL-10）并未减少。在缺血性损伤后不久施用单剂量卡格列净可减轻 AKI 并减弱有害促炎细胞因子的释放外伤或手术后。这些发现表明卡格列净在减轻肾 IRI 影响方面具有潜在的新治疗作用，值得进一步研究。版权所有 © 2024 作者。由 Wolters Kluwer Health, Inc. 出版

We investigated the potential of acute canagliflozin administration to mitigate acute kidney injury (AKI) and attenuate deleterious pro-inflammatory cytokine release in a clinically relevant swine model of severe renal ischemia reperfusion injury (IRI) induced by hemorrhage and aortic occlusion.Long-term canagliflozin use attenuates renal function decline and reduces AKI in diabetes mellitus and heart failure patients. Whilst several reports indicate prophylactic SGLT2 inhibition prevents AKI in IRI, the efficacy of acute administration on IRI and inflammation is not known.Female swine (n=16) underwent controlled hemorrhage of 25% blood volume, followed by 90 min of aortic occlusion at the level of the renal ostia (via Resuscitative Endovascular Balloon Occlusion of the Aorta). A single 300 mg dose of oral canagliflozin or vehicle (saline) was delivered 5 mins into aortic occlusion. Hemodynamic monitoring, markers of renal function (serum creatinine, blood urea nitrogen, proteinuria and urinary neutrophil gelatinase-associated lipocalin) and serum cytokine concentrations (including interleukins: IL-1RA, IL-6, IL-8, IL-10, IL-18; and Tumor necrosis factor alpha) were analyzed after IRI, and during a 6h critical care phase.Compared to controls, animals receiving canagliflozin had less severe AKI, improved creatinine clearance, reduced proteinuria, and significantly lower tubular damage as evidenced by histopathology and urinary NGAL. Furthermore, the pro-inflammatory cytokine IL-6 was markedly attenuated without reduction in anti-inflammatory cytokines (IL-1RA and IL-10).A single dose of canagliflozin administered shortly into ischemic insult mitigates AKI and attenuates harmful pro-inflammatory cytokine release following trauma or surgery. These findings suggest a potential novel therapeutic role for canagliflozin in mitigating the effects of renal IRI worthy of further investigation.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.