Legumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmn(WT) and lgmn(KO) mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-alpha, CCL-2, IL-33, and IL-1 alpha. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H(2)DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmn(KO) mRTECs compared with lgmn(WT) control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.
Ferroptosis (NULL)
Autophagy (自噬)
Chaperone-Mediated Autophagy (NULL)
Tumor Necrosis Factor-alpha (肿瘤坏死因子α)
Interleukin-1alpha (α白细胞介素1)
Acute Kidney Injury (Acute Kidney Injury)
Interleukin-33 (NULL)
Staining and Labeling (染色与标记)
Urea (尿素)
Epithelial Cells (上皮细胞)
Blood (血液)
Ischemia (缺血)
Arteries (动脉)
Blood Urea Nitrogen (血尿素氮)
Serum (血清)
Kidney (肾)
Interleukin-1 (白细胞介素1)
Nitrogen (氮)
Peroxidase (过氧化物酶)
Phospholipid Hydroperoxide Glutathione Peroxidase (NULL)
Homeostasis (内环境稳定)
Oxygen (氧)
Reperfusion (再灌注)
Immunoprecipitation (免疫沉淀法)
Cells (细胞)
Reactive Oxygen Species (活性氧)
Wounds and Injuries (创伤和损伤)
Survival (幸存)
Maintenance (保养,检修,坚持,维持)
Mice (小鼠)
Glutathione Peroxidase (谷胱甘肽过氧化酶)
Hematology (血液学)
Therapeutics (治疗学,治疗法,治疗)
Hypoxia ()
Reperfusion Injury (再灌注损伤)
Glutathione (谷胱甘肽)
Inflammation (炎症)
Organization and Administration (组织和管理)
Role (角色)
Creatinine (肌酸酐)
Index (NULL)
Renal Artery (肾动脉)
Folic Acid (叶酸)
[1]Nankai Univ, Sch Med, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China.
[2]Beijing Univ Chinese Med, Dongfang Hosp, Beijing 100078, Peoples R China.
[3]Tianjin Univ, Tianjin Key Lab Modern Drug Delivery & High Effic, Tianjin 300072, Peoples R China.
(8.0+极速模式)