ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury

Wang, Yue; Zhang, Menghan; Bi, Ran; Su, Yali; Quan, Fei; Lin, Yining; Yue, Chongxiu; Cui, Xinmeng; Zhao, Qixiang; Liu, Siliang; Yang, Yong; Zhang, Dayong; Cao, Qiu-Hua; Gao, Xinghua

doi:10.1016/j.redox.2022.102262

Cited by 146 publications

(87 citation statements)

References 64 publications

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“…FPN1 protein was also significantly overexpressed by 190% in FECD tissues when compared with control tissues (p < 0.001; Fig.1G). Acyl-CoA synthetase long chain member family 4 (ACSL4), a key player in cell death including ferroptosis, is responsible for regulating lipid biosynthesis by converting fatty acid to fatty acyl-CoA esters (68, 69). ACSL4 gene expression was downregulated by 0.46-fold in FECD tissues in comparison to control tissues (p < 0.05; Fig.1H), which indicates cells downregulating lipid peroxidation precursors ***.…”

Section: Resultsmentioning

confidence: 99%

“…1G). Acyl-CoA synthetase long chain member family 4 (ACSL4), a key player in cell death including ferroptosis, is responsible for regulating lipid biosynthesis by converting fatty acid to fatty acyl-CoA esters (68,69). ACSL4 gene expression was downregulated by 0.46-fold in FECD tissues in comparison to control tissues (p < 0.05; Fig.…”

Section: Fecd Surgical Samples Demonstrate Key Markers Of Ferroptosis...mentioning

confidence: 98%

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TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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Fuchs endothelial corneal dystrophy (FECD), a progressive polygenic disease that causes degeneration of the corneal endothelium, is the leading indication for corneal transplantation in the U.S. Characteristically, loss of corneal endothelial cells and formation of degenerative extracellular guttae result in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor. FECD pathogenesis is linked to oxidative stress and environmental exposure to ultraviolet A (UVA), and impaired endogenous response to oxidative stress is common to the disease across multiple genotypes. UV irradiation is also known to cause cellular damage by ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation. Although a possible role for ferroptosis in FECD has been postulated to account for the increased susceptibility to oxidative damage and lipid peroxidation, this has not been explored systematically. In this study, we investigated the roles of genetic background and UVA exposure in causing lipid membrane damage and endothelial cell degeneration in FECD. We first sought clinical evidence of iron-mediated lipid peroxidation in surgical samples obtained from FECD patients undergoing endothelial keratoplasty, and found increased levels of cytosolic ferrous iron (Fe2+) and evidence of lipid peroxidation were present in end-stage diseased tissues compared with healthy human donor corneas. Next, using immortalized (F35T) and primary cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found that alterations in gene and protein expression involved in ferroptosis were conserved in both cell culture and tissue models of FECD disease compared to controls, including elevated levels of the ferroptosis-specific marker transferrin receptor 1. F35T immortalized cells showed significantly higher basal lipid peroxidation than control HCEC-B4G12 cells, indicating higher susceptibility to ferroptosis attributable to genetic background. Then, we tested the impact of physiologically relevant doses of UVA irradiation on F35T cell cultures and found increased cytosolic Fe2+ iron levels indicating a role for ferroptosis in FECD disease progression. Finally, we tested the effects of inhibitory ferroptosis molecules. We found that F35T cells were more prone to RSL3 induced ferroptosis than healthy controls with deferoxamine chelation which indicated increased susceptibility in FECD cells, and cell death could be prevented after experimentally-induced ferroptosis using solubilized antioxidant ubiquinol indicating a role for anti-ferroptosis therapies. This investigation demonstrates that FECD genetic background and UVA exposure contribute to basal and incidental iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated oxidative damage and disease progression in FECD.

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Section: Resultsmentioning

confidence: 99%

Section: Fecd Surgical Samples Demonstrate Key Markers Of Ferroptosis...mentioning

confidence: 98%

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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“…Ding et al reported that microRNAs also participated in the regulation of ferroptosis in an IRI-AKI mouse model ( Ding et al, 2020 ). Additionally, Wang et al showed ACSL4 knockout significanlty inhibited the ferroptosis of renal tubular epithelial cells in IRI-AKI mice, which indicated ACSL4 might be a key target for AKI treatment ( Wang et al, 2022 ). XJB-5-131 is a new generation of antioxidant, which exerts dual effects of mitochondrial targeting and free radical scavenging.…”

Section: Ferroptosis Is Involved In the Development Of Akimentioning

confidence: 99%

Ferroptosis and Acute Kidney Injury (AKI): Molecular Mechanisms and Therapeutic Potentials

Feng

Qiao

et al. 2022

Front. Pharmacol.

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Acute kidney injury (AKI), a common and serious clinical kidney syndrome with high incidence and mortality, is caused by multiple pathogenic factors, such as ischemia, nephrotoxic drugs, oxidative stress, inflammation, and urinary tract obstruction. Cell death, which is divided into several types, is critical for normal growth and development and maintaining dynamic balance. Ferroptosis, an iron-dependent nonapoptotic type of cell death, is characterized by iron overload, reactive oxygen species accumulation, and lipid peroxidation. Recently, growing evidence demonstrated the important role of ferroptosis in the development of various kidney diseases, including renal clear cell carcinoma, diabetic nephropathy, and AKI. However, the exact mechanism of ferroptosis participating in the initiation and progression of AKI has not been fully revealed. Herein, we aim to systematically discuss the definition of ferroptosis, the associated mechanisms and key regulators, and pharmacological progress and summarize the most recent discoveries about the role and mechanism of ferroptosis in AKI development. We further conclude its potential therapeutic strategies in AKI.

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“…The β-actin was applied as an internal control. The relative expression of target genes was analyzed using the 2 -ΔΔCt approach [12]. The following primers were used: MMP-2 (forward: 5′ -GATACCCCTTTGACGGTAAGGA-3′, reverse: 5′ -CCTTCTCCCAAGGTCCATAGC-3′); MMP-9 (forward: 5′-ACGCACGACGTCTTCCAGTA-3′, reverse: 5′ -CCACCTGGTTCAACTCACTCC-3′); PCNA (forward: 5′ -CCTGCTGGGATATTAGCTCCA-3′, reverse: 5′ -CAGCGGTAGGTGTCGAAGC-3′); HIF-1α (forward: 5′-TGACTGTGCACCTACTATGTCACTT-3′, reverse: 5′-GGTCAGCTGTGGGTAATCCACTC-3′); COX-2 (forward: 5′-TGACTGTGCACCTACTATGTCACTT-3′, reverse: 5′-GGTCAGCTGTGGGTAATCCACTC-3′); GADPH (forward: 5′-GCACCGTCAAGGCTGAGAAC-3′, reverse: 5′-ATGGTGGTGAGACGCCAGT-3′).…”

Section: 3rt-pcr Analysismentioning

confidence: 99%

The protective effects of Azilsartan against hypoxia in endometrial stromal cells: an implication in endometriosis

et al. 2022

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IntroductionEndometriosis is a reproductive disorder closely associated with hypoxia stress. Increasing evidences have implied the important roles of angiotensin II (ANG II) receptors in the pathophysiology of endometriosis. Thus, we speculated that Azilsartan (AZL), an ANG II receptor blocker, might have an effective function in controlling endometriosis.Material and methodsThe endometriotic animal model was established in female SD rats (6-8 weeks old, 200-220 g). Rats were divided into sham group and endometriosis (EMS) group. Rats in EMS group were anaesthetized by halothane and a mid-ventral incision was performed to expose the bowels. Human endometrial stromal cell line T-HESC was used for the in vitro assays. The T-HESC cells were cultured in DMEM-F12 mediumwith 10% fetal bovine serum (FBS, Hyclone), and 4 mM L-glutamine, 0.25% HEPES plus necessary antibiotics (Sigma-Aldrich, USA), at 37°C in a humidified atmosphere of 5% CO2.ResultsThe results show that upregulation of ANG II type 1 (AT1) receptor was observed in the endometriotic rat models. Treatment with AZL prevented the development of endometriotic lesions and suppressed the expressions of HIF-1α and cyclooxygenase 2 (COX-2) in endometriotic rats. In vitro assays proved that hypoxia-induced proliferation, migration, and invasion of T-HESC cells were attenuated by AZL. AZL inhibited the expression levels of hypoxia-inducible factor-1α (HIF-1α), COX-2, and prostaglandin E2 (PGE2) production in hypoxia-induced T-HESC cells. Overexpression of HIF-1α blocked the effects of AZL on T-HESC cells in response to hypoxia.ConclusionsAZL showed therapeutic function on endometriosis through inhibiting hypoxia-induced cell proliferation, migration, and invasion of T-HESC cells via HIF-1α/COX-2/PGE2 signaling.

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ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury

Cited by 146 publications

References 64 publications

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Ferroptosis and Acute Kidney Injury (AKI): Molecular Mechanisms and Therapeutic Potentials

The protective effects of Azilsartan against hypoxia in endometrial stromal cells: an implication in endometriosis

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