Melatonin Alleviates Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis

Abstract

Acute kidney injury (AKI) is still a puzzling clinical problem; its pathophysiology is not completely understood. Up to now, an effective treatment for AKI is lacking. Ferroptosis is a novel form of regulated cell death characterized by the lethal accumulation of lipid hydroperoxides that are dependent on iron and reactive oxygen species and mitochondrial dysfunction. Recently, ferroptosis was shown to play a vital role in AKI such as ischemia-reperfusion kidney injury and folic acid-induced AKI. Melatonin (MT) is an antioxidant that regulates the sleep-wake cycle. While the therapeutic effect of melatonin on AKI has been reported, its mechanism for the treatment of renal ferroptosis remains unclear. We found that melatonin treatment significantly alleviated the serum biochemistry index and histopathological alterations in vivo AKI models induced by bilateral renal artery ischemia reperfusion and folic acid in mice. Ferroptosis induced by hypoxia and reoxygenation or erastin (Era) in mouse tubular epithelial cells (MTEC) was also rescued by melatonin treatment. RNA sequence analysis of ferroptosis-related genes showed that melatonin affects oxidative stress responses by inhibiting hypoxia and reoxygenation- (HR-) mediated downregulation of NRF2 and upregulation of Slc7a11 in MTEC. Specific knockdown of NRF2 increased the sensitivity of cells to ferroptosis, and melatonin failed to protect against ferroptosis in the HR condition. Together, our data indicate that melatonin prevents ferroptosis in AKI by acting on the NRF2/Slc7a11 axis.

Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis

“…Inducible Gpx4 knockout mice directly aggravate lipid-oxidation-induced acute kidney injury and associated death [33]. Melatonin treatment significantly alleviates ischemia reperfusion-induced ferroptosis and acute kidney injury [47]. Folic acid induces ferroptosis, not necroptosis, in acute kidney injury [27], which can be rescued by quercetin through inactivation of transcription factor 3 [28].…”

Ferroptosis Regulated by Hypoxia in Cells

“…In addition to HIFs, NRF2, the master regulator of oxidative stress signaling, also plays an important role in hypoxia-induced ferroptosis. Many studies reported that NRF mediates the regulation of ferroptosis induced by hypoxia or H/R [ 124 , 125 , 128 , 138 ], while another group of studies reported that targeting NRF2 could inhibit hypoxia-or H/R-induced ferroptosis [ 149 , 160 , 161 , 162 , 163 , 164 , 165 , 166 ].…”

“…Additionally, dimethyl fumarate, a therapeutic agent for relapsing-remitting multiple sclerosis, inhibits H/R-induced ferroptosis in alpha mouse liver cells and a mouse liver IRI model by activating NRF2 pathway [ 163 ]. Melatonin, an antioxidant that regulates the sleep-wake cycle, was reported to inhibit RSL3-, erastin-, or H/R-induced ferroptosis through modulating NRF2, AKT, and GPX4, in hypoxic-ischemic brain damage, as well as through upregulating NRF2 and downregulating SLC7A11 in mouse tubular epithelial cells and a mouse acute kidney injury (AKI) model [ 164 , 165 ]. Moreover, gastrodin, one of the main functional substances of functional food raw material Gastrodia elata BI , inhibited hypoxia- or erastin-induced ferroptosis in hippocampal neurons by activating NRF2 and GPX4, as well as inhibiting KEAP1 and COX-2 [ 166 ].…”

Ferroptosis: A new insight for treatment of acute kidney injury

“…Treatment with the GPX4 inhibitor RSL3 eliminates the protective effect of irisin ( Zhang et al, 2021b ). Melatonin and entacapone were confirmed to upregulate the nuclear translocation of Nrf2, resulting in increased expression of the downstream SLC7A11 and significant suppression of oxidative stress and ferroptosis ( Yang et al, 2022b ; Huang et al, 2022 ). Recent research revealed that dexmedetomidine could attenuate ferroptosis-mediated IRI-induced AKI by inhibiting ACSL4 ( Tao et al, 2022 ), and ACSL4 knockout also significantly alleviated this injury ( Wang et al, 2022b ).…”