Department of Physics, College of Arts and Sciences, University of South Florida, Tampa, FL 33620, USA.
Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL 33620, USA.
Sci Transl Med. 2022 Mar 9;14(635):eabj4906. doi: 10.1126/scitranslmed.abj4906.
Renal ischemia-reperfusion injury is an important contributor to the development of delayed graft function after transplantation, which is associated with higher rejection rates and poorer long-term outcomes. One of the earliest impairments during ischemia is Na/K-ATPase (Na/K pump) dysfunction due to insufficient ATP supply, resulting in subsequent cellular damage. Therefore, strategies that preserve ATP or maintain Na/K pump function may limit the extent of renal injury during ischemia-reperfusion. Here, we applied a synchronization modulation electric field to activate Na/K pumps, thereby maintaining cellular functions under ATP-insufficient conditions. We tested the effectiveness of this technique in two models of ischemic renal injury: an in situ renal ischemia-reperfusion injury model (predominantly warm ischemia) and a kidney transplantation model (predominantly cold ischemia). Application of the synchronization modulation electric field to a renal ischemia-reperfusion injury mouse model preserved Na/K pump activity, thereby reducing kidney injury, as reflected by 40% lower plasma creatinine (1.17 ± 0.03 mg/dl) in the electric field-treated group as compared to the untreated control group (1.89 ± 0.06 mg/dl). In a mouse kidney transplantation model, renal graft function was improved by more than 50% with the application of the synchronization modulation electric field according to glomerular filtration rate measurements (85.40 ± 12.18 μl/min in the untreated group versus 142.80 ± 11.65 μl/min in the electric field-treated group). This technique for preserving Na/K pump function may have therapeutic potential not only for ischemic kidney injury but also for other diseases associated with Na/K pump dysfunction due to inadequate ATP supply.
肾缺血再灌注损伤是移植后延迟肾功能恢复的重要原因，与更高的排斥率和更差的长期预后相关。缺血过程中最早的损伤之一是由于 ATP 供应不足导致的 Na/K-ATP 酶（Na/K 泵）功能障碍，从而导致随后的细胞损伤。因此，保留 ATP 或维持 Na/K 泵功能的策略可能会限制缺血再灌注期间肾损伤的程度。在这里，我们应用同步调制电场来激活 Na/K 泵，从而在 ATP 不足的情况下维持细胞功能。我们在两种缺血性肾损伤模型中测试了这种技术的有效性：原位肾缺血再灌注损伤模型（主要为温热性缺血）和肾移植模型（主要为冷缺血）。将同步调制电场应用于肾缺血再灌注损伤小鼠模型中，可维持 Na/K 泵的活性，从而减轻肾脏损伤，表现为电场处理组的血浆肌酐（1.17±0.03mg/dl）比未处理对照组（1.89±0.06mg/dl）低 40%。在小鼠肾移植模型中，根据肾小球滤过率测量，应用同步调制电场可使肾移植物功能提高 50%以上（未处理组为 85.40±12.18μl/min，电场处理组为 142.80±11.65μl/min）。这种维持 Na/K 泵功能的技术不仅对缺血性肾损伤具有治疗潜力，而且对其他由于 ATP 供应不足导致 Na/K 泵功能障碍的疾病也具有治疗潜力。
