Nuciferine protects against folic acid‐induced acute kidney injury by inhibiting ferroptosis

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.

Nephroprotective Role of Chrysophanol in Hypoxia/Reoxygenation-Induced Renal Cell Damage via Apoptosis, ER Stress, and Ferroptosis

“…Quercetin (QCT) was reported to inhibit ferroptosis, but not apoptosis, necrosis, or autophagy, in renal proximal tubular epithelial cells and ameliorate AKI induced by I/R or folic acid (FA) [ 43 ]. In this study, chrysophanol attenuated H/R-induced ferroptosis via the regulation of GPX4 and SLC7A11, as seen on Western blot ( Figure 2 B) and BODIPY C11 fluorescence staining ( Figure 3 ) in HK-2 cells, similar to the results obtained in other studies [ 44 , 45 ]. Therefore, chrysophanol ameliorated renal cell injury with H/R, perhaps by inhibiting ferroptosis.…”

Tectorigenin protects against unilateral ureteral obstruction by inhibiting Smad3‐mediated ferroptosis and fibrosis

“…As evidenced by Figure S1a,b, erastin treated dramatically provoked the overproduction of ROS and lipid ROS, while tectorigenin intervention markedly ameliorated the excessive ROS and lipid ROS in a dependent manner. Moreover, we also evaluated the role of tectorigenin in iron overload by calcein‐AM, a fluorescent probe for monitoring labile iron pool (Li et al, 2021). As shown in Figure S1c, erastin treatment markedly impeded the fluorescence signals, whereas tectorigenin treatment reversed the fluorescence signals, indicating that tectorigenin treatment prevents iron accumulation during ferroptosis.…”

“…The contents of intracellular ROS, lipid ROS, and cellular labile iron were determined as mentioned previously (Li et al, 2021). In brief, TECs were incubated with indicated probes in 5% CO 2 and 37°C for 30 min (H2DCF‐DA for ROS, Beyotime; the BODIPY 581/591 C11 for lipid ROS, thermo; Calcein‐AM, Beyotime) after treatment.…”

Ferritinophagy‐Mediated Ferroptosis Involved in Paraquat‐Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD

“…Iron homeostasis played an important role in maintaining cellular function. Systemic and cellular iron metabolism is mediated by iron intake, storage, utilization, and efflux and regulated by multiple proteins including ferritin, TfR1, DMT1, and FpN1 [45]. Excess iron usually was stored in ferritin to eliminate the toxicity of iron.…”