Recent in vivo studies suggest that heme Fe causes proximal tubular lipid peroxidation and cytotoxicity, thereby contributing to the pathogenesis of myoglobinuric (Mgb) acute renal failure. Because hydroxyl radical (.OH) scavengers [dimethylthiourea (DMTU), benzoate, mannitol] can mitigate this injury, it is postulated that .OH is a mediator of Mgb-induced renal damage. The present study has tested these hypotheses using an isolated rat proximal tubular segment (PTS) system. An equal mixture of Fe2+/Fe3+ (4 mM total), when added to PTS, caused marked cytotoxicity [as defined by lactate dehydrogenase (LDH) release] and lipid peroxidation [assessed by malondialdehyde (MDA) increments]. Fe2+ or Fe3+ alone each induced massive MDA elevations, but only Fe2+ caused cytotoxicity. Although both DMTU and benzoate decreased LDH release during the Fe2+/Fe3+ challenge, mannitol and GSH did not, despite equivalent reductions in .OH (gauged by the salicylate trap method). GSH and catalase (but not DMTU, benzoate, or mannitol) decreased MDA concentrations, suggesting the Fe-driven lipid peroxidation was more H2O2 than .OH dependent. Deferoxamine totally blocked Fe-induced LDH release, even under conditions in which it caused an apparent increase in .OH generation. Mgb paradoxically protected against Fe-mediated PTS injury, an effect largely reproduced by albumin. In conclusion, these data suggest that: (a) Fe can cause PTS lipid peroxidation and cytotoxicity by a non-.OH-dependent mechanism; (b) Fe-mediated cytotoxicity and lipid peroxidation are not necessarily linked; and (c) Mgb paradoxically protects PTS against Fe-mediated injury, suggesting that: (i) Mgb Fe may require liberation from its porphyrin ring before exerting toxicity; and (ii) the protein residue may blunt the resulting injury.
R A Zager, C A Foerder
Title and authors | Publication | Year |
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The protective properties of resveratrol against glycerol-induced acute kidney injury in rats
Baghishani M, Mehri S, Aminifard T, Jafarian A, Hosseinzadeh H |
Avicenna Journal of Phytomedicine | 2025 |
Rhabdomyolysis, Acute Kidney Injury, and Mortality in Ebola Virus Disease: Retrospective Analysis of Cases From the Eastern Democratic Republic of the Congo, 2019
Kasereka MC, Mukadi-Bamuleka D, Kitenge-Omasumbu R, Edidi-Atani F, Kuamfumu MM, Mulangu S, Tshiani-Mbaya O, Malengera Vicky K, Mbala-Kingebeni P, Ahuka-Mundeke S, Muyembe-Tamfum JJ, Lee BE, Houston S, Mumtaz Z, Hawkes MT |
The Journal of Infectious Diseases | 2024 |
Advances in the Mechanistic Study of the Control of Oxidative Stress Injury by Modulating HDAC6 Activity
Xue Y, Gan B, Zhou Y, Wang T, Zhu T, Peng X, Zhang X, Zhou Y |
Cell Biochemistry and Biophysics | 2023 |
NRF2, a Superstar of Ferroptosis
Yan R, Lin B, Jin W, Tang L, Hu S, Cai R |
Antioxidants | 2023 |
Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damage
S Zhao, X Wang, X Zheng, X Liang, Z Wang, J Zhang, X Zhao, S Zhuang, Q Pan, F Sun, W Shang, J Barasch, A Qiu |
Free radical biology & medicine | 2021 |
Ferrotoxicity and Its Amelioration by Calcitriol in Cultured Renal Cells
C Annamalai, R Seth, P Viswanathan, A Rahman |
Analytical cellular pathology (Amsterdam) | 2021 |
Ferroptosis and Necroptosis in the Kidney
A Belavgeni, C Meyer, J Stumpf, C Hugo, A Linkermann |
Cell Chemical Biology | 2020 |
Oxidative stress and inflammasome activation in human rhabdomyolysis-induced acute kidney injury
A Grivei, KT Giuliani, X Wang, J Ungerer, L Francis, K Hepburn, GT John, PF Gois, AJ Kassianos, H Healy |
Free radical biology & medicine | 2020 |
Rhabdomyolysis-Induced AKI Was Ameliorated in NLRP3 KO Mice via Alleviation of Mitochondrial Lipid Peroxidation in Renal Tubular Cells
SJ Song, S Kim, S Lee, JY Moon, HS Hwang, JS Kim, SH Park, KH Jeong, YG Kim |
International journal of molecular sciences | 2020 |
Effectiveness of deferiprone-loaded nanocarrier in experimentally induced rhabdomyolysis: A dose-comparison study
RR Rashed, NM Deghiedy, RM El-Hazek, WA El-Sabbagh, ER Rashed, MA El-Ghazaly |
Bioorganic chemistry | 2020 |
Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis
KT Giuliani, AJ Kassianos, H Healy, PH Gois |
International journal of molecular sciences | 2019 |
Fluid resuscitation with preventive peritoneal dialysis attenuates crush injury-related acute kidney injury and improves survival outcome
XL Zhou, SZ Ni, D Xiong, XQ Cheng, P Xu, Y Zhao |
Scandinavian journal of trauma, resuscitation and emergency medicine | 2019 |
Origin and Consequences of Necroinflammation
M Sarhan, WG Land, W Tonnus, CP Hugo, A Linkermann |
Physiological reviews | 2018 |
Immunological consequences of kidney cell death
M Sarhan, A von Mässenhausen, C Hugo, R Oberbauer, A Linkermann |
Cell Death and Disease | 2018 |
Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features, pathophysiology and treatment
SI Kokoris, E Gavriilaki, A Miari, Α Travlou, E Kyriakou, A Anagnostopoulos, E Grouzi |
Hematology | 2018 |
Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury
Y Shi, L Xu, J Tang, L Fang, S Ma, X Ma, J Nie, X Pi, A Qiu, S Zhuang, N Liu |
American journal of physiology. Renal physiology | 2017 |
Myoglobinemia markers with potential applications in forensic sample analysis: lipid markers in myoglobinemia for postmortem blood
H Abe, D Yajima, Y Hoshioka, A Nara, S Nagasawa, H Iwase |
International Journal of Legal Medicine | 2017 |
Acute Alcohol Intoxication Exacerbates Rhabdomyolysis-Induced Acute Renal Failure in Rats
JP Tsai, CJ Lee, YM Subeq, RP Lee, BG Hsu |
International journal of medical sciences | 2017 |
Redox and peroxidase activities of the hemoglobin superfamily – relevancy to health and disease
BJ Reeder |
Antioxidants & Redox Signaling | 2016 |
Rabdomiolisi traumatiche e non traumatiche
S Mrozek, T Geeraerts |
EMC - Anestesia-Rianimazione | 2016 |
Rabdomiólisis traumáticas y no traumáticas
S Mrozek, T Geeraerts |
EMC - Anestesia-Reanimación | 2016 |
Marked Protection Against Acute Renal and Hepatic Injury Following Nitrited- Myoglobin + Tin Protoporphyrin Administration
RA Zager |
Translational Research | 2015 |
Renoprotective effect of long acting thioredoxin by modulating oxidative stress and macrophage migration inhibitory factor against rhabdomyolysis-associated acute kidney injury
K Nishida, H Watanabe, S Ogaki, A Kodama, R Tanaka, T Imafuku, Y Ishima, VT Chuang, M Toyoda, M Kondoh, Q Wu, M Fukagawa, M Otagiri, T Maruyama |
Scientific Reports | 2015 |
Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review
N Petejova, A Martinek |
Critical Care | 2014 |
Myoglobinuria in Autopsy Pathology: Relevant and Potentially Unrecognized
MM Blessing, RR Reichard, JJ Maleszewski, MP Alexander |
Academic Forensic Pathology | 2014 |
Urine catalytic iron and neutrophil gelatinase-associated lipocalin as companion early markers of acute kidney injury after cardiac surgery: a prospective pilot study
K Akrawinthawong, MK Shaw, J Kachner, EO Apostolov, AG Basnakian, S Shah, J Tilak, PA McCullough |
Cardiorenal Medicine | 2013 |
Myoglobin-Induced Apoptosis: Two Pathways Related to Endoplasmic Reticulum Stress : A Substitutive Pathway of Endoplasmic Reticulum Stress-Induced Apoptosis
J Zhou, D Kong, X Zhang, Y Wang, Z Feng, X Zhang, L Zhang, Y Wang, Y Xie, X Chen |
Therapeutic Apheresis and Dialysis | 2012 |
Renal Replacement Therapy in Acute Kidney Failure due to Rhabdomyolysis
G Maggi, FQ Hinojosa, MJ Villagran, EG Arévalo, FG Rodríguez |
Case Reports in Critical Care | 2012 |
Clinico-Pathological Conference on Acute Kidney Injury in a Patient with Nephrotic Syndrome
R Orozco, FC Fervenza, L Contreras, N Leung, A Singh, JA Fierro |
Nephron Clinical Practice | 2011 |
Rhabdomyolysis in the Intensive Care Unit
ML Shapiro, A Baldea, FA Luchette |
Journal of Intensive Care Medicine | 2011 |
Rhabdomyolysis and Acute Kidney Injury
X Bosch, E Poch, JM Grau |
New England Journal of Medicine | 2009 |
ROLE OF CHELATABLE IRON VS. MYOGLOBIN IN OXIDATIVE STRESS AFTER CRUSH TRAUMA
S Rehberg, C Thiemermann, MO Maybauer |
Shock | 2009 |
Zn2+, derived from cell preparation, partly attenuates Ca2+-dependent cell death induced by A23187, calcium ionophore, in rat thymocytes
Y Sakanashi, TM Oyama, Y Matsuo, TB Oyama, Y Nishimura, S Ishida, S Imai, Y Okano, Y Oyama |
Toxicology in Vitro | 2009 |
Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria
EY Plotnikov, AA Chupyrkina, IB Pevzner, NK Isaev, DB Zorov |
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2009 |
Ultrastructural and Histopathological Analysis of Initial Change and Myoglobin Absorption on Proximal Tubule Injury with Glycerol-induced Rhabdomyolysis in Rats
T Abe, M Inoue, M Furutani, M Akita, K Setsu |
Journal of Hard Tissue Biology | 2009 |
Myoglobin Induces Oxidative Stress and Decreases Endocytosis and Monolayer Permissiveness in Cultured Kidney Epithelial Cells without Affecting Viability
SN Parry, N Ellis, Z Li, P Maitz, PK Witting |
Kidney and Blood Pressure Research | 2008 |
Clinical Nephrotoxins
ME Broe, GA Porter, WM Bennett, G Deray |
2008 | |
Hypoxia inducible factor-1 modulates hemin-induced IL-8 secretion in microvascular endothelium
R Natarajan, BJ Fisher, AA Fowler |
Microvascular Research | 2007 |
Comparison of Cytotoxicity of Cysteine and Homocysteine for Renal Epithelial Cells
T Nakanishi, ER Akabane, M Nanami, Y Kiyobayashi, R Moriguchi, Y Hasuike, Y Otaki, K Miyagawa, R Itahana, M Izumi |
Nephron Experimental Nephrology | 2005 |
Factors Affecting Urinary Myoglobin Stability In Vitro
Z Chen-Levy, MH Wener, B Toivola, P Daum, M Reyes, JS Fine |
American Journal of Clinical Pathology | 2005 |
Effects of Amifostine on Glycerol-Pretreated Rabbit Kidneys
S Barun, D Ertoy, E Dilekoz, S Muftuoglu, Y Erten, G Sucak, M Bali, N Tekeli, Y Sarioglu, ZS Ercan |
Basic & Clinical Pharmacology & Toxicology | 2005 |
Parenteral iron compounds sensitize mice to injury-initiated TNF-α mRNA production and TNF-α release
RA Zager, AC Johnson, SY Hanson, S Lund |
American journal of physiology. Renal physiology | 2005 |
Desferrioxamine Inhibits Production of Cytotoxic Heme to Protein Cross-Linked Myoglobin: A Mechanism to Protect against Oxidative Stress without Iron Chelation
BJ Reeder, MT Wilson |
Chemical Research in Toxicology | 2005 |
Renal Siderosis in Donor Allograft: Pathologic and Clinical Sequelae
S Salim, H Asad, MS Kumar, J Brezin, M Heifets, B Fyfe |
American Journal of Transplantation | 2004 |
Molecular Mechanism of Oxalate-Induced Free Radical Production and Glutathione Redox Imbalance in Renal Epithelial Cells: Effect of Antioxidants
T Rashed, M Menon, S Thamilselvan |
American Journal of Nephrology | 2004 |
Mechanism of in vitro heme-induced LDL oxidation: effects of antioxidants
K Klouche, M Morena, B Canaud, B Descomps, JJ Beraud, JP Cristol |
European Journal of Clinical Investigation | 2004 |
Radiographic contrast media-induced tubular injury: Evaluation of oxidant stress and plasma membrane integrity
RA Zager, AC Johnson, SY Hanson |
Kidney International | 2003 |
Evolution of Total Antioxidant Status in a Model of Acute Renal Insufficiency in Rats
A Fernández-Fúnez, FJ Polo, L Broseta, MP Atienza, A Mora, FG Gascón |
Renal Failure | 2003 |
Parenteral iron formulations: A comparative toxicologic analysis and mechanisms of cell injury
RA Zager, AC Johnson, SY Hanson, H Wasse |
American Journal of Kidney Diseases | 2002 |
In reply to Van Wyck
R Zager |
American Journal of Kidney Diseases | 2002 |
Renal cortical cholesterol accumulation is an integral component of the systemic stress response
RA Zager, A Johnson |
Kidney International | 2001 |
Role of glomerular nitric oxide in glycerol-induced acute renal failure
JM Valdivielso, JM López-Novoa, N Eleno, FP Barriocanal |
Canadian Journal of Physiology and Pharmacology | 2000 |
HUMAN RED BLOOD CELL HEMOLYSATE IS A POTENT MITOGEN FOR RENAL TUBULAR EPITHELIAL CELLS
RJ Anderson, CJ Ray, TJ Burke |
Renal Failure | 2000 |
Acute Renal Failure in an Adult Patient with Henoch-Schoenlein Purpura After Episode of Macroscopic Hematuria
S Michail, C Stathakis, L Nakopoulou, K Aroni, K Revenas, K Avdikou, G Vaiopoulos |
Renal Failure | 1999 |
Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack
RA Zager, KM Burkhart |
Kidney International | 1998 |
A Causative Role for Redox Cycling of Myoglobin and Its Inhibition by Alkalinization in the Pathogenesis and Treatment of Rhabdomyolysis-induced Renal Failure
KP Moore, SG Holt, RP Patel, DA Svistunenko, W Zackert, D Goodier, BJ Reeder, M Clozel, R Anand, CE Cooper, JD Morrow, MT Wilson, V Darley-Usmar, LJ Roberts |
The Journal of biological chemistry | 1998 |
Evidence suggesting that nitric oxide mediates iron-induced toxicity in cultured proximal tubule cells
L Chen, BH Zhang, DC Harris |
American journal of physiology. Renal physiology | 1998 |
Myoglobin toxicity in proximal human kidney cells: Roles of Fe, Ca2+, H2O2, and terminal mitochondrial electron transport
RA Zager, K Burkhart |
Kidney International | 1997 |
Acute Renal Failure Due to Rhabdomyolysis in Diabetic Patients
EM Higa, SA Dib, JR Martins, L Campos, E Homsi |
Renal Failure | 1997 |
Therapeutic Strategies in the Prevention of Acute Renal Failure
RE García |
Renal Failure | 1997 |
Decreased expression of mitochondrial-derived H2O2 and hydroxyl radical in cytoresistant proximal tubules
RA Zager, K Burkhart |
Kidney International | 1997 |
Rhabdomyolysis and myohemoglobinuric acute renal failure
RA Zager |
Kidney International | 1996 |
Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria
RA Zager |
Kidney International | 1996 |
Differential cytoprotection by glycine against oxidant damage to proximal tubule cells
K Sogabe, NF Roeser, MA Venkatachalam, JM Weinberg |
Kidney International | 1996 |
Effect of iron on renal tubular epithelial cells
HT Sponsel, AC Alfrey, WS Hammond, JA Durr, C Ray, RJ Anderson |
Kidney International | 1996 |
Evidence for cytochrome P-450 as a source of catalytic iron in myoglobinuric acute renal failure
R Baliga, Z Zhang, M Baliga, SV Shah |
Kidney International | 1996 |
Evaluation of Myoglobin Clearance during Continuous Hemofiltration in a Swine Model of Acute Renal Failure
DP Nicolau, YJ Feng, AH Wu, SP Bernstein, CH Nightingale |
The International Journal of Artificial Organs | 1996 |
Molecular Biology of Membrane Transport Disorders
SG Schultz, TE Andreoli, AM Brown, DM Fambrough, JF Hoffman, MJ Welsh |
1996 | |
Induction of nodular sclerosis by insulin in rat mesangial cells in vitro: Studies of collagen
CK Abrass, D Spicer, GJ Raugi |
Kidney International | 1995 |
Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury
RA Zager, KM Burkhart, DS Conrad, DJ Gmur |
Kidney International | 1995 |
Heme protein-mediated renal injury: A protective role for 21-aminosteroids in vitro and in vivo
KA Nath, J Balla, AJ Croatt, GM Vercellotti |
Kidney International | 1995 |
Obstruction of proximal tubules initiates cytoresistance against hypoxic damage
RA Zager |
Kidney International | 1995 |
Heme protein-induced tubular cytoresistance: Expression at the plasma membrane level
RA Zager |
Kidney International | 1995 |
The “green water” syndrome: Copper-induced hemolysis and subsequent acute renal failure as consequence of a religious ritual
E Sontz, J Schwieger |
The American Journal of Medicine | 1995 |
Renal antioxidant enzymes: Their regulation and function
I Ichikawa, S Kiyama, T Yoshioka |
Kidney International | 1994 |
Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties
B Fuhrman, J Oiknine, M Aviram |
Atherosclerosis | 1994 |
Iron Loading Enhances Susceptibility to Renal Ischemia in Rats
ZL Wu, MS Palter |
Renal Failure | 1994 |
Acute renal failure in the setting of bone marrow transplatation
RA Zager |
Kidney International | 1994 |
H<sub>2</sub>O<sub>2</sub>‐induced oxidative injury in rat cardiac myocytes is not potentiated by 1,1,1‐trichloroethane, carbon tetrachloride, or halothane
M Toraason, I Heinroth‐Hoffmann, D Richards, M Woolery, P Hoffmann |
Journal of Toxicology and Environmental Health | 1994 |
Inorganic iron effects on in vitro hypoxic proximal renal tubular cell injury
RA Zager, BA Schimpf, CR Bredl, DJ Gmur |
Journal of Clinical Investigation | 1993 |
Physiological pH. Effects on posthypoxic proximal tubular injury
RA Zager, BA Schimpf, DJ Gmur |
Circulation research | 1993 |
Intracellular myoglobin loading worsens H2O2-induced, but not hypoxia/reoxygenation-induced, in vitro proximal tubular injury
RA Zager |
Circulation research | 1993 |
Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications
RA Zager |
Journal of Clinical Investigation | 1992 |
Direct amphotericin B-mediated tubular toxicity: Assessments of selected cytoprotective agents
RA Zager, CR Bredl, BA Schimpf |
Kidney International | 1992 |