PGE2 pathway mediates oxidative stress‐induced ferroptosis in renal tubular epithelial cells

Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H2O2, the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin‐1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)‐1 and COX‐2 were up‐regulated. Meanwhile, the expression of microsomal prostaglandin E synthase‐2 was elevated, whereas the expression of microsomal prostaglandin E synthase‐1 and cytosolic prostaglandin E synthase were down‐regulated. Furthermore, the expression of 15‐hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX‐2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E‐series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4‐methylenedioxyamphetamine, Fe2+ accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress‐induced ferroptosis in renal tubular epithelial cells.

[1]  Lei Wang,et al.  Fucoxanthin Attenuates Oxidative Damage by Activating the Sirt1/Nrf2/HO-1 Signaling Pathway to Protect the Kidney from Ischemia-Reperfusion Injury , 2022, Oxidative medicine and cellular longevity.

[2]  Ying Su,et al.  Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis , 2021, Frontiers in Immunology.

[3]  Junjian Zhang,et al.  Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway. , 2021, International immunopharmacology.

[4]  H. Ping,et al.  Ceria Nanoparticles Ameliorate Renal Fibrosis by Modulating the Balance Between Oxidative Phosphorylation and Aerobic Glycolysis , 2021 .

[5]  G. Kroemer,et al.  Broadening horizons: the role of ferroptosis in cancer , 2021, Nature Reviews Clinical Oncology.

[6]  Nai-Feng Liu,et al.  Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. , 2021, Free radical biology & medicine.

[7]  J. Iovanna,et al.  Combating pancreatic cancer chemoresistance by triggering multiple cell death pathways. , 2021, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[8]  Xuan Li,et al.  Ferroptosis and cardiovascular disease: role of free radical-induced lipid peroxidation , 2021, Free radical research.

[9]  A. Dehghan,et al.  Association between COX‐2 and 15‐PGDH polymorphisms and SLE susceptibility , 2020, International journal of rheumatic diseases.

[10]  Kerong Hai,et al.  The Critical Role of Cannabinoid Receptor 2 in URB602-induced Protective Effects Against Renal Ischemia-Reperfusion Injury in the Rat. , 2020, Shock.

[11]  Shi-kun Yang,et al.  VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis , 2020, Cell Death & Disease.

[12]  Y. Kanwar,et al.  Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. , 2019, The Journal of clinical investigation.

[13]  C. Ronco,et al.  Mitochondria in Sepsis-Induced AKI. , 2019, Journal of the American Society of Nephrology : JASN.

[14]  W. Xiong,et al.  Oxidative Stress and Renal Fibrosis: Mechanisms and Therapies. , 2019, Advances in experimental medicine and biology.

[15]  F. Schweda,et al.  The renal vasodilatory effect of prostaglandins is ameliorated in isolated-perfused kidneys of endotoxemic mice , 2018, Pflügers Archiv - European Journal of Physiology.

[16]  S. Swaminathan,et al.  Iron Homeostasis Pathways as Therapeutic Targets in Acute Kidney Injury , 2018, Nephron.

[17]  N. Thomson.  Targeting oxidant‐dependent mechanisms for the treatment of respiratory diseases and their comorbidities , 2018, Current opinion in pharmacology.

[18]  B. Stockwell,et al.  Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease , 2017, Cell.

[19]  K. Hosohata.  Role of Oxidative Stress in Drug-Induced Kidney Injury , 2016, International journal of molecular sciences.

[20]  B. Guo,et al.  Protective Effect of Rutin Against H2O2-Induced Oxidative Stress and Apoptosis in Human Lens Epithelial Cells , 2016, Current eye research.

[21]  Yaping Zhang,et al.  Evaluation of Vitamin C Supplementation on Kidney Function and Vascular Reactivity Following Renal Ischemic Injury in Mice , 2016, Kidney and Blood Pressure Research.

[22]  P. Vandenabeele,et al.  Regulated necrosis: disease relevance and therapeutic opportunities , 2016, Nature Reviews Drug Discovery.

[23]  B. Ratliff,et al.  Oxidant Mechanisms in Renal Injury and Disease. , 2016, Antioxidants & redox signaling.

[24]  N. Al-Dhabi,et al.  Pyrrolidine Dithiocarbamate Inhibits NF-KappaB Activation and Upregulates the Expression of Gpx1, Gpx4, Occludin, and ZO-1 in DSS-Induced Colitis , 2015, Applied Biochemistry and Biotechnology.

[25]  Keith A. Johnson,et al.  Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE , 2015, Nature Communications.

[26]  R. Thiele,et al.  AKI associated with cardiac surgery. , 2015, Clinical journal of the American Society of Nephrology : CJASN.

[27]  A. Walch,et al.  Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice , 2014, Nature Cell Biology.

[28]  D. Green,et al.  Synchronized renal tubular cell death involves ferroptosis , 2014, Proceedings of the National Academy of Sciences.

[29]  M. R. Lamprecht,et al.  Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death , 2012, Cell.

[30]  L. MacMillan-Crow,et al.  Role of Mitochondrial Oxidants in an In Vitro Model of Sepsis-Induced Renal Injury , 2012, Journal of Pharmacology and Experimental Therapeutics.

[31]  J. Bonventre,et al.  Cellular pathophysiology of ischemic acute kidney injury. , 2011, The Journal of clinical investigation.

[32]  K. Dunn,et al.  Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. , 2011, Journal of the American Society of Nephrology : JASN.

[33]  Hai-ying Liu,et al.  Amelioration of cisplatin nephrotoxicity by genetic or pharmacologic blockade of prostaglandin synthesis. , 2011, Kidney international.

[34]  P. Krause,et al.  Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances. , 2010, The international journal of biochemistry & cell biology.

[35]  M. Rosner,et al.  Acute kidney injury. , 2009, Current drug targets.

[36]  B. Stockwell,et al.  Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. , 2008, Chemistry & biology.

[37]  P. Dagher,et al.  Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent. , 2007, American journal of physiology. Renal physiology.

[38]  Ralf Morgenstern,et al.  Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target , 2007, Pharmacological Reviews.

[39]  Philip R Mayeux,et al.  Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. , 2007, Journal of the American Society of Nephrology : JASN.

[40]  S. Narumiya,et al.  Prostaglandin E Receptors* , 2007, Journal of Biological Chemistry.

[41]  G. Chiappara,et al.  Role of prostaglandin E2 in the invasiveness, growth and protection of cancer cells in malignant pleuritis. , 2006, European journal of cancer.

[42]  T. P. Pretlow,et al.  15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis , 2006, Proceedings of the National Academy of Sciences.

[43]  H. Tai,et al.  NAD+-linked 15-hydroxyprostaglandin dehydrogenase: structure and biological functions. , 2006, Current pharmaceutical design.

[44]  H. Tai,et al.  15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer* , 2005, Journal of Biological Chemistry.

[45]  Ralf Morgenstern,et al.  Human Microsomal Prostaglandin E Synthase-1 , 2003, Journal of Biological Chemistry.

[46]  Y. Sugimoto,et al.  Prostanoid receptor subtypes. , 2002, Prostaglandins & other lipid mediators.

[47]  H. Tai,et al.  Prostaglandin catabolizing enzymes. , 2002, Prostaglandins & other lipid mediators.

[48]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[49]  S. Narumiya,et al.  Prostanoid receptors: structures, properties, and functions. , 1999, Physiological reviews.

[50]  F. Pichaud,et al.  Chromosomal localization of the type-I 15-PGDH gene to 4q34–q35 , 1997, Human Genetics.