Danyu Li1, Bing Liu1, Yumei Fan1, Ming Liu1, Bihui Han1, Yanxiu Meng1, Xiao Xu1, Zhiyuan Song2, Xiaopeng Liu1,3, Qiang Hao1, Xianglin Duan1, Akira Nakai4, Yanzhong Chang1, Pengxiu Cao1, Ke Tan1. 1. Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, China. 2. Department of Neurosurgery, Handan Central Hospital, Handan, China. 3. Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China. 4. Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube, Japan.
Abstract
BACKGROUND AND PURPOSE: Acute kidney injury is a common clinical problem with no definitive or specific treatment. Therefore, the molecular mechanisms of acute kidney injury must be fully understood to develop novel treatments. Nuciferine, a major bioactive compound isolated from the lotus leaf, possesses extensive pharmacological activities. Its effect on folic acid-induced acute kidney injury, however, remains unknown. Here, we aimed to clarify the pharmacological effects of nuciferine and its mechanisms of action in acute kidney injury. EXPERIMENTAL APPROACH: The effects of nuciferine on folic acid-induced acute kidney injury in mice were investigated. HK-2 human proximal tubular epithelial cells and HEK293T HEK cells were used to evaluate the protective effect of nuciferine on RSL3-induced ferroptosis. KEY RESULTS: Nuciferine treatment mitigated the pathological alterations, ameliorated inflammatory cell infiltration and improved kidney dysfunction in mice with folic acid-induced acute kidney injury. In HK-2 and HEK293T cells, nuciferine significantly prevented RSL3-induced ferroptotic cell death. Mechanistically, nuciferine significantly inhibited ferroptosis by preventing iron accumulation and lipid peroxidation in vitro and in vivo. Moreover, knockdown of glutathione (GSH) peroxidase 4 (GPX4) abolished the protective effect of nuciferine against ferroptosis. CONCLUSION AND IMPLICATIONS: Nuciferine ameliorated renal injury in mice with acute kidney injury, perhaps by inhibiting the ferroptosis. Nuciferine may represent a novel treatment that improves recovery from acute kidney injury by targeting ferroptosis.
BACKGROUND AND PURPOSE: Acute kidney injury is a common clinical problem with no definitive or specific treatment. Therefore, the molecular mechanisms of acute kidney injury must be fully understood to develop novel treatments. Nuciferine, a major bioactive compound isolated from the lotus leaf, possesses extensive pharmacological activities. Its effect on folic acid-induced acute kidney injury, however, remains unknown. Here, we aimed to clarify the pharmacological effects of nuciferine and its mechanisms of action in acute kidney injury. EXPERIMENTAL APPROACH: The effects of nuciferine on folic acid-induced acute kidney injury in mice were investigated. HK-2 human proximal tubular epithelial cells and HEK293T HEK cells were used to evaluate the protective effect of nuciferine on RSL3-induced ferroptosis. KEY RESULTS: Nuciferine treatment mitigated the pathological alterations, ameliorated inflammatory cell infiltration and improved kidney dysfunction in mice with folic acid-induced acute kidney injury. In HK-2 and HEK293T cells, nuciferine significantly prevented RSL3-induced ferroptotic cell death. Mechanistically, nuciferine significantly inhibited ferroptosis by preventing iron accumulation and lipid peroxidation in vitro and in vivo. Moreover, knockdown of glutathione (GSH) peroxidase 4 (GPX4) abolished the protective effect of nuciferine against ferroptosis. CONCLUSION AND IMPLICATIONS: Nuciferine ameliorated renal injury in mice with acute kidney injury, perhaps by inhibiting the ferroptosis. Nuciferine may represent a novel treatment that improves recovery from acute kidney injury by targeting ferroptosis.