Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA.
Department of Surgery, The University of North Carolina, Chapel Hill, NC, 27599, USA.
Redox Biol. 2020 May;32:101504. doi: 10.1016/j.redox.2020.101504. Epub 2020 Mar 10.
Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), a potentially fatal syndrome characterized by a rapid decline in kidney function. Excess production of superoxide contributes to the injury. We hypothesized that oral administration of a high dose of vitamin B12 (B12 - cyanocobalamin), which possesses a superoxide scavenging function, would protect kidneys against IRI and provide a safe means of treatment. Following unilateral renal IR surgery, C57BL/6J wild type (WT) mice were administered B12 via drinking water at a dose of 50 mg/L. After 5 days of the treatment, plasma B12 levels increased by 1.2-1.5x, and kidney B12 levels increased by 7-8x. IRI mice treated with B12 showed near normal renal function and morphology. Further, IRI-induced changes in RNA and protein markers of inflammation, fibrosis, apoptosis, and DNA damage response (DDR) were significantly attenuated by at least 50% compared to those in untreated mice. Moreover, the presence of B12 at 0.3 μM in the culture medium of mouse proximal tubular cells subjected to 3 hr of hypoxia followed by 1 hr of reperfusion in vitro showed similar protective effects, including increased cell viability and decreased reactive oxygen species (ROS) level. We conclude that a high dose of B12 protects against perfusion injury both in vivo and in vitro without observable adverse effects in mice and suggest that B12 merits evaluation as a treatment for I/R-mediated AKI in humans.
肾缺血/再灌注损伤 (IRI) 是急性肾损伤 (AKI) 的主要原因，AKI 是一种潜在致命的综合征，其特征是肾功能迅速下降。过量的超氧化物产生导致损伤。我们假设，口服大剂量维生素 B12（B12-氰钴胺），其具有超氧化物清除功能，可保护肾脏免受 IRI 影响，并提供一种安全的治疗方法。在单侧肾 IRI 手术后，C57BL/6J 野生型 (WT) 小鼠通过饮用水给予 B12，剂量为 50mg/L。治疗 5 天后，血浆 B12 水平增加 1.2-1.5 倍，肾脏 B12 水平增加 7-8 倍。接受 B12 治疗的 IRI 小鼠肾功能和形态接近正常。此外，与未治疗的小鼠相比，IRI 诱导的炎症、纤维化、细胞凋亡和 DNA 损伤反应 (DDR) 的 RNA 和蛋白质标志物的变化至少减弱了 50%。此外，在体外培养的小鼠近端肾小管细胞中，培养基中存在 0.3μM 的 B12，在缺氧 3 小时后再灌注 1 小时，表现出类似的保护作用，包括增加细胞活力和降低活性氧 (ROS) 水平。我们得出结论，高剂量的 B12 可在体内和体外防止灌注损伤，而在小鼠中没有观察到不良反应，并表明 B12 值得作为人类 I/R 介导的 AKI 的治疗方法进行评估。
