Ferrostatin‐1 modulates dysregulated kidney lipids in acute kidney injury

Abstract

Ferroptosis, a form of regulated necrosis characterized by peroxidation of lipids such as arachidonic acid‐containing phosphatidylethanolamine (PE), contributes to the pathogenesis of acute kidney injury (AKI). We have characterized the kidney lipidome in an experimental nephrotoxic AKI induced in mice using folic acid and assessed the impact of the ferroptosis inhibitor Ferrostatin‐1. Matrix‐assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to assess kidney lipidomics and it discriminated between glomeruli, medulla, and cortex in control kidneys, AKI kidneys, and AKI + Ferrostatin‐1 kidneys. Out of 139 lipid species from 16 classes identified, 29 (20.5%) showed significant differences between control and AKI at 48 h. Total PE and lyso‐sulfatide species decreased, while phosphatidylinositol (PI) species increased in AKI. Dysregulated mRNA levels for Pemt, Pgs1, Cdipt, and Tamm41, relevant to lipid metabolism, were in line with the lipid changes observed. Ferrostatin‐1 prevented AKI and some AKI‐associated changes in lipid levels, such as the decrease in PE and lyso‐sulfatide species, without changing the gene expression of lipid metabolism enzymes. In conclusion, changes in the kidney lipid composition during nephrotoxic AKI are associated with differential gene expression of lipid metabolism enzymes and are partially prevented by Ferrostatin‐1. © 2022 The Pathological Society of Great Britain and Ireland.

Regulated cell death pathways in kidney disease

“…However, in one study, specific targeting of bone marrow-derived RIPK3 induced an early decrease in kidney inflammation independent of effects on tubule cell death and did not improve kidney function 48 h after administration of folic acid 65 , suggesting that RIPK3 might have a dual role in FA-AKI by promoting both early inflammation through its function in innate immune cells and later tubule cell necroptosis in response to inflammatory cytokines through its function in tubular cells. FA-AKI has also been used as a model to explore the effect of ferroptosis on the lipidome 103 , 117 , 175 .…”

Novel Insight into Ferroptosis in Kidney Diseases

“…Research has also been published on the dysregulation of kidney lipids in AKI. Of the 139 lipid species from 16 classes identified, 29 (20.5%) showed significant differences between AKI and the control at 48 h [41]. Phosphatidylinositol (PI) species increased in AKI, but total phosphatidylethanolamine (PE) and lyso-sulfatide species decreased [41].…”

Emerging Potential Therapeutic Targets of Ferroptosis in Skeletal Diseases

“…In addition, Fer-1 can inhibit osteoblast ferroptosis by regulating the Nrf2-ARE signaling pathway, thereby alleviating nanoparticle-induced peri-implant osteolysis [ 53 ]. In comparison with Fer-1, new-generation ferrostatins (SRS 11–92 and SRS 16–86) have the advantages of improving the stability of metabolism and tremendously preventing diseases such as acute kidney injury and ischemia-reperfusion injury [ 54 , 55 ].…”