Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

叶酸引起的急性肾损伤不完全恢复是进展为慢性肾病的主要危险因素。线粒体功能障碍被认为是急性肾损伤中适应不良修复的关键因素。用 FG-4592（一种缺氧诱导因子脯氨酰羟化酶抑制剂）治疗正在成为一种减轻肾损伤的新方法。然而，潜在的机制尚未完全阐明。目前的研究表明，在 FA 给药后第 7 天，FG-4592 对肾功能不全和组织病理学损伤具有保护作用。FG-4592 通过促进肾小管细胞再生来加速肾小管修复，表现为细胞核抗原阳性肾小管细胞增殖增加，并促进结构完整性，正如上皮细胞间紧密连接分子occludin-1和粘附连接分子E-钙粘蛋白的上调所反映的那样。此外，FG-4592 通过恢复功能相关蛋白水通道蛋白 1、水通道蛋白 2 和氯化钠协同转运蛋白来改善肾小管功能恢复。具体而言，FG-4592 预处理在叶酸注射后第 7 天抑制了缺氧诱导因子 1α 的活化，从而改善了超微结构异常，促进了 ATP 的产生，并减弱了肾组织和线粒体中过量的活性氧的产生。这主要是由线粒体动力学的平衡介导的，如线粒体裂变 1 和动力相关蛋白 1 的下调以及 mitofusin 1 和视神经萎缩 1 的上调所示。此外，FG-4592 预处理可减轻肾小管上皮细胞死亡、肾脏炎症和随后的间质纤维化。在体外，FG-4592预处理可以改善TNF-α诱导的HK-2细胞损伤。总之，我们的研究结果支持 FG-4592 对叶酸诱导的线粒体功能障碍的保护作用。因此，FG-4592 治疗可用作促进肾小管修复和减轻急性肾损伤进展的有用策略。