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Kidney International Dec 2022Hemopexin, a heme scavenging protein, accumulates in the kidneys during acute kidney injury (AKI). However, the function of this accumulated hemopexin in the kidney is...
Hemopexin, a heme scavenging protein, accumulates in the kidneys during acute kidney injury (AKI). However, the function of this accumulated hemopexin in the kidney is unclear. In both the cisplatin-induced and the unilateral kidney ischemia-reperfusion injury models of AKI, we found accumulation of hemoglobin and hemopexin in the kidneys localized to the proximal tubules. Next, hemopexin wild-type and knockout mice were compared in both AKI models and hemopexin wild type mice had significantly worse kidney injury. Furthermore, there was increased kidney expression of kidney injury molecule-1 (a biomarker of AKI) and heme oxygenase-1 (an indicator of oxidative stress) in hemopexin wild type compared with knockout mice in both models of AKI. Next, the interaction of hemopexin and hemoglobin in vitro was investigated using cultured proximal tubular cells. Co-incubation of hemopexin with hemoglobin resulted in hemoglobin deposition and exaggerated hemoglobin-induced injury. Deferoxamine, an iron chelator, and ferrostatin-1, a ferroptosis inhibitor, inhibited this deleterious effect of hemoglobin and hemopexin in proximal tubular cells, implicating iron toxicity in the mechanism of hemopexin mediated injury. Furthermore, the protective effect of deferoxamine in cisplatin-induced AKI was apparent in hemopexin wild type, but not in hemopexin knockout mice, further implicating hemopexin as a mediator of iron toxicity in AKI. Thus, our findings demonstrate that hemopexin accumulates in the kidneys and worsens kidney injury in AKI by increasing hemoglobin deposition on proximal tubular cells to exaggerate hemoglobin-induced cell injury.
Topics: Mice; Animals; Hemopexin; Cisplatin; Deferoxamine; Acute Kidney Injury; Kidney Tubules, Proximal; Kidney; Mice, Knockout; Hemoglobins; Iron; Mice, Inbred C57BL; Kidney Tubules
PubMed: 36007598
DOI: 10.1016/j.kint.2022.07.024 -
International Journal of Molecular... Jan 2022Hemopexin is the plasma protein with the highest affinity for heme. Seminal studies have highlighted its role in different kinds of heme-associated disorders, but its...
Hemopexin is the plasma protein with the highest affinity for heme. Seminal studies have highlighted its role in different kinds of heme-associated disorders, but its implication in cancer has been neglected for a long time. Considering the emerging importance of heme in tumors, the present review proposes an update of the works investigating hemopexin involvement in cancer, with the attempt to stimulate further future studies on this topic.
Topics: Disease Progression; Hemopexin; Humans; Membrane Transport Proteins; Neoplasms; Receptors, Virus
PubMed: 35055182
DOI: 10.3390/ijms23020997 -
Methods in Enzymology 1988
Review
Topics: Amino Acid Sequence; Amino Acids; Animals; Carbohydrates; Chromatography, Affinity; Hemopexin; Humans; Indicators and Reagents; Molecular Sequence Data
PubMed: 3070302
DOI: 10.1016/0076-6879(88)63049-7 -
International Journal of Molecular... Jun 2021Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative... (Review)
Review
Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.
Topics: Anemia, Sickle Cell; Animals; Cytoprotection; Hemopexin; Humans; Immunomodulation; Lipoproteins; Microvessels
PubMed: 34203861
DOI: 10.3390/ijms22126408 -
Science Advances Dec 2022Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with...
Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients ( = 30) and replicated key findings in a second cohort ( = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.
Topics: Animals; Female; Mice; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Doxorubicin; Hemopexin
PubMed: 36563141
DOI: 10.1126/sciadv.adc9245 -
Clinica Chimica Acta; International... Oct 2001Hemopexin is a heme-binding plasma glycoprotein which, after haptoglobin, forms the second line of defense against hemoglobin-mediated oxidative damage during... (Comparative Study)
Comparative Study Review
BACKGROUND
Hemopexin is a heme-binding plasma glycoprotein which, after haptoglobin, forms the second line of defense against hemoglobin-mediated oxidative damage during intravascular hemolysis. A decrease in plasma hemopexin concentration reflects a recent release of heme compounds in the extracellular compartment. Heme-hemopexin complexes are delivered to hepatocytes by receptor-mediated endocytosis after which hemopexin is recycled to the circulation.
METHODS OF ANALYSIS
Immunonephelometric and -turbidimetric hemopexin assays are available as more precise and rapid alternatives to the radial immunodiffusion technique.
INTERPRETATIONS
Hemopexin determinations are not subject to interference by in vitro hemolysis. Altered serum or plasma concentrations of hemopexin are found not only in hemolytic anemias but also in other conditions such as chronic neuromuscular diseases and acute intermittent porphyria. In laboratory medicine, while hemopexin determination in tandem with haptoglobin has potential applications in the assessment of intravascular hemolysis and allows for the monitoring of the severity of hemolysis after depletion of haptoglobin, its diagnostic utility is less clear in other pathological conditions. Further studies are necessary to fully establish the clinical significance of hemopexin determination.
Topics: Antioxidants; Chemistry, Clinical; Genetic Heterogeneity; Heme; Hemopexin; Homeostasis; Humans; Iron; Receptors, Peptide; Reference Values
PubMed: 11580905
DOI: 10.1016/s0009-8981(01)00586-1 -
Journal of Leukocyte Biology Apr 2007The heme-binding hemopexin consists of two, four-bladed propeller domains connected by a linker region. Hemopexin domains are found in different species on the... (Review)
Review
The heme-binding hemopexin consists of two, four-bladed propeller domains connected by a linker region. Hemopexin domains are found in different species on the phylogenetic tree and in the human species represented in hemopexin, matrix metalloproteinases (MMPs), vitronectin, and products of the proteoglycan 4 gene. Hemopexin and hemopexin domains of human proteins fulfill functions in activation of MMPs, inhibition of MMPs, dimerization, binding of substrates or ligands, cleavage of substrates, and endocytosis by low-density lipoprotein receptor-related protein-1 (LRP-1; CD91) and LRP-2 (megalin, GP330). Insights into the structures and functions of hemopexin (domains) form the basis for positive or negative interference with the formation of molecular complexes and hence, might be exploited therapeutically in inflammation, cancer, and wound healing.
Topics: Amino Acid Sequence; Dimerization; Enzyme Activation; Hemopexin; Humans; Ligands; Matrix Metalloproteinases; Models, Biological; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Structure-Activity Relationship
PubMed: 17185359
DOI: 10.1189/jlb.1006629 -
Frontiers in Immunology 2020Hemopexin is the main plasmatic scavenger of cell-free heme, released in the context of intravascular hemolysis or major cell injury. Heme is indispensable for the...
Hemopexin is the main plasmatic scavenger of cell-free heme, released in the context of intravascular hemolysis or major cell injury. Heme is indispensable for the oxygen transport by hemoglobin but when released outside of the erythrocytes it becomes a danger-associated molecular pattern, contributing to tissue injury. One of the mechanisms of pro-inflammatory action of heme is to activate the innate immune complement cascade. Therefore, we hypothesized that injection of hemopexin will prevent hemolysis-induced complement activation. Human plasma-derived hemopexin is compatible with the heme clearance machinery of the mice. 100 or 500 mg/kg of hemopexin was injected in C57Bl/6 mice before treatment with phenylhydrazine (inducer of erythrocytes lysis) or with PBS as a control. Blood was taken at different timepoints to determine the pharmacokinetic of injected hemopexin in presence and absence of hemolysis. Complement activation was determined in plasma, by the C3 cleavage (western blot) and in the kidneys (immunofluorescence). Kidney injury was evaluated by urea and creatinine in plasma and renal NGAL and HO-1 gene expression were measured. The pharmacokinetic properties of hemopexin (mass spectrometry) in the hemolytic mice were affected by the target-mediated drug disposition phenomenon due to the high affinity of binding of hemopexin to heme. Hemolysis induced complement overactivation and signs of mild renal dysfunction at 6 h, which were prevented by hemopexin, except for the NGAL upregulation. The heme-degrading capacity of the kidney, measured by the HO-1 expression, was not affected by the treatment. These results encourage further studies of hemopexin as a therapeutic agent in models of diseases with heme overload.
Topics: Animals; Complement Activation; Hemolysis; Hemopexin; Humans; Kidney; Mice; Mice, Inbred C57BL
PubMed: 32849588
DOI: 10.3389/fimmu.2020.01684 -
Antioxidants & Redox Signaling Feb 2010Hemopexin is an acute-phase plasma glycoprotein, produced mainly by the liver and released into plasma, where it binds heme with high affinity. Other sites of hemopexin... (Review)
Review
Hemopexin is an acute-phase plasma glycoprotein, produced mainly by the liver and released into plasma, where it binds heme with high affinity. Other sites of hemopexin synthesis are the nervous system, skeletal muscle, retina, and kidney. The only known receptor for the heme-hemopexin complex is the scavenger receptor, LDL receptor-related protein (LRP)1, which is expressed in most cell types, thus indicating multiple sites of heme-hemopexin complex recovery. The better-characterized function of hemopexin is heme scavenging at the systemic level, consisting of the transport of heme to the liver, where it is catabolyzed or used for the synthesis of hemoproteins or exported to bile canaliculi. This is important both in physiologic heme management for heme-iron recycling and in pathologic conditions associated with intravascular hemolysis to prevent the prooxidant and proinflammatory effects of heme. Other than scavenging heme, the heme-hemopexin complex has been shown to be able to activate signaling pathways, thus promoting cell survival, and to modulate gene expression. In this review, the importance of heme scavenging by hemopexin, as well as the other emerging functions of this protein, are discussed.
Topics: Animals; Heme; Hemopexin; Humans; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Models, Biological; Protein Binding; Signal Transduction
PubMed: 19650691
DOI: 10.1089/ars.2009.2787 -
Acta Haematologica Polonica 1971
Review
Topics: Adult; Age Factors; Aged; Animals; Beta-Globulins; Child; Child, Preschool; Enzyme Induction; Female; Haptoglobins; Heme; Hemolysis; Hemopexin; Humans; Immunoelectrophoresis; Infant; Infant, Newborn; Liver; Male; Middle Aged; Pregnancy; Rats; Splenectomy; Thalassemia
PubMed: 4122077
DOI: No ID Found