Abstract
Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.
Highlights
Acute Kidney Injury (AKI) is referred as a transient decline of renal function, which confers the severe clinical syndrome associated with high mortality (Bellomo et al, 2012)
To determine whether lipoic acid (LA) supplementation could protect against Folic acid (FA)-induced renal damage, histological analysis was evaluated with hematoxylin and eosin (H&E) and Periodic acid-Schiff (PAS) staining
Tubular injuries were assessed by quantification of HE-stained sections and revealed significantly increased tubulointerstitial injury scores in mice injected with FA injection, which were reduced by LA supplementation in a dose-dependent manner, but without statistical significance
Summary
Acute Kidney Injury (AKI) is referred as a transient decline of renal function, which confers the severe clinical syndrome associated with high mortality (Bellomo et al, 2012). Despite unpredictable in most cases, the occurrence of AKI is significantly higher in severe I/R injury after kidney transplant surgery, cisplatin for tumor chemotherapy, or contrast media for radiography and so on, especially for the susceptible individuals, including old age and patients with diabetes mellitus or CKD (Zhang et al, 2020). This highlighted the urgent need for novel therapeutic approaches that aims at preventing and/ or reversing its sequelae (Zhao et al, 2018). Folic acid (FA)-induced AKI is one of the typical models simulating drug or toxicant-induced tubular injury, which is closely related to crystal formation in the tubule lumen and cellular oxidative stress, leading to massive inflammatory reaction and eventually tubular cell death (Martin-Sanchez et al, 2018)
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