Involvement of Hemopexin in the Pathogenesis of Proteinuria in Children with Idiopathic Nephrotic Syndrome

Pukajło-Marczyk, Agnieszka; Zwołińska, Danuta

doi:10.3390/jcm10143160

Cited by 13 publications

(9 citation statements)

References 51 publications

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“…Apolipoproteins, vitronectin, hemopexin and gelsolin reflect the process of active damage to podocytes [ 24 , 25 , 26 , 32 , 34 , 38 , 39 , 40 , 46 , 47 , 48 , 49 , 50 , 51 ]. Apolipoprotein A-1 (ApoA-1), a small 28 kDa high-density lipoprotein (HDL) component, is considered as a putative permeability factor [ 32 , 34 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease

Chebotareva

Vinogradov

Brzhozovskiy

et al. 2022

IJMS

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Primary focal segmental glomerulosclerosis (FSGS), along with minimal change disease (MCD), are diseases with primary podocyte damage that are clinically manifested by the nephrotic syndrome. The pathogenesis of these podocytopathies is still unknown, and therefore, the search for biomarkers of these diseases is ongoing. Our aim was to determine of the proteomic profile of urine from patients with FSGS and MCD. Patients with a confirmed diagnosis of FSGS (n = 30) and MCD (n = 9) were recruited for the study. For a comprehensive assessment of the severity of FSGS a special index was introduced, which was calculated as follows: the first score was assigned depending on the level of eGFR, the second score—depending on the proteinuria level, the third score—resistance to steroid therapy. Patients with the sum of these scores of less than 3 were included in group 1, with 3 or more—in group 2. The urinary proteome was analyzed using liquid chromatography/mass spectrometry. The proteome profiles of patients with severe progressive FSGS from group 2, mild FSGS from group 1 and MCD were compared. Results of the label free analysis were validated using targeted LC-MS based on multiple reaction monitoring (MRM) with stable isotope labelled peptide standards (SIS) available for 47 of the 76 proteins identified as differentiating between at least one pair of groups. Quantitative MRM SIS validation measurements for these 47 proteins revealed 22 proteins with significant differences between at least one of the two group pairs and 14 proteins were validated for both comparisons. In addition, all of the 22 proteins validated by MRM SIS analysis showed the same direction of change as at the discovery stage with label-free LC-MS analysis, i.e., up or down regulation in MCD and FSGS1 against FSGS2. Patients from the FSGS group 2 showed a significantly different profile from both FSGS group 1 and MCD. Among the 47 significantly differentiating proteins, the most significant were apolipoprotein A-IV, hemopexin, vitronectin, gelsolin, components of the complement system (C4b, factors B and I), retinol- and vitamin D-binding proteins. Patients with mild form of FSGS and MCD showed lower levels of Cystatin C, gelsolin and complement factor I.

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Section: Discussionmentioning

confidence: 99%

Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease

Chebotareva

Vinogradov

Brzhozovskiy

et al. 2022

IJMS

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“…Another application of hemopexin is to prevent acute adverse effects in blood transfusions after prolonged storage of red blood cells (RBC); transfusion of prolonged packed RBC can increase morbidity and mortality in trauma-induced hemorrhage, mainly by alterations to the RBC and hemolysis [ 23 ]. Hx can be administered intravenously but has potential side effects caused by its structure and protease activity [ 24 , 25 , 26 ]. Thus, it is crucial to map only heme-binding sites in the Hx structure, to abolish potential risky side effects.…”

Section: Discussionmentioning

confidence: 99%

New Insights into Hemopexin-Binding to Hemin and Hemoglobin

Lechuga

Napoleão-Pêgo

Morel

et al. 2022

IJMS

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Hemopexin (Hx) is a plasma glycoprotein that scavenges heme (Fe(III) protoporphyrin IX). Hx has important implications in hemolytic disorders and hemorrhagic conditions because releasing hemoglobin increases the labile heme, which is potentially toxic, thus producing oxidative stress. Therefore, Hx has been considered for therapeutic use and diagnostics. In this work, we analyzed and mapped the interaction sequences of Hx with hemin and hemoglobin. The spot-synthesis technique was used to map human hemopexin (P02790) binding to hemin and human hemoglobin. A library of 15 amino acid peptides with a 10-amino acid overlap was designed to represent the entire coding region (aa 1-462) of hemopexin and synthesized onto cellulose membranes. An in silico approach was taken to analyze the amino acid frequency in the identified interaction regions, and molecular docking was applied to assess the protein-protein interaction. Seven linear peptide sequences in Hx were identified to bind hemin (H1–H7), and five were described for Hb (Hb1–Hb5) interaction, with just two sequences shared between hemin and Hb. The amino acid composition of the identified sequences demonstrated that histidine residues are relevant for heme binding. H105, H293, H373, H400, H429, and H462 were distributed in the H1–H7 peptide sequences, but other residues may also play an important role. Molecular docking analysis demonstrated Hx’s association with the β-chain of Hb, with several hotspot amino acids that coordinated the interaction. This study provides new insights into Hx-hemin binding motifs and protein-protein interactions with Hb. The identified binding sequences and specific peptides can be used for therapeutic purposes and diagnostics as hemopexin is under investigation to treat different diseases and there is an urgent need for diagnostics using labile heme when monitoring hemolysis.

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“…Another application of hemopexin is to prevent acute adverse effects in blood transfusions after prolonged storage of red blood cells (RBC); transfusion of prolonged packed RBC can increase morbidity and mortality in trauma-induced hemorrhage, mainly by alterations in RBC and hemolysis [22]. Hx can be administered intravenously but have potential side effects caused by its structure and protease activity [23][24][25]. Thus, it is crucial to map only heme-binding sites in the Hx structure, to abolish potential risky side effects.…”

Section: Discussionmentioning

confidence: 99%

New Insights on Hemopexin Binding to Hemin and Hemoglobin

De-Simone¹,

Lechuga²,

Napoleão-Pêgo³

et al. 2022

Preprint

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Background: Hemopexin (Hx) is a plasma glycoprotein that scavenges heme (Fe(III) protoporphyrin IX), Hx have important implication in hemolytic disorders and hemorrhagic condition because the release of hemoglobin increase labile heme, which is potentially toxic producing oxidative stress. Hx has been considered for therapeutic use and diagnostics. In this work, we analyzed and mapped interaction sequences of Hx with hemin and hemoglobin (2) Methods: Spot-synthesis technique was used to map human hemopexin (P02790) binding to hemin and human hemoglobin, a library of 15 amino acid peptides with a 10-amino acid overlap was designed to represent the entire coding region (aa 1-462) of hemopexin and synthesized onto cellulose membranes. In silico approach was performed to analyze amino acid frequency in identified interaction regions, and molecular docking was applied for protein-protein interaction (3) Results: Seven linear peptide sequences in Hx were identified to bind hemin (H1-H7), and five were described for Hb (Hb1-Hb5) interaction, with just two sequences shared between hemin and Hb. Amino acid composition of identified sequences demonstrated that Histidine residues are relevant for heme binding, H105, H293, H373, H400, H429, and H462 was distributed in H1-H7 peptide sequences, but other residues may also play an important role. Molecular docking analysis demonstrated Hx association with the β-chain of Hb, with several hot spot amino acids that coordinated interaction. (4) Conclusions: This study highlights new insights on Hx-hemin binding motifs and protein-protein interactions with Hb. Binding sequences and identified specific peptides can be used for therapeutic purposes and diagnostics, as hemopexin is under investigation to treat different diseases, and there is an urgent need for diagnostics of labile heme for monitoring hemolysis.

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Involvement of Hemopexin in the Pathogenesis of Proteinuria in Children with Idiopathic Nephrotic Syndrome

Cited by 13 publications

References 51 publications

Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease

Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease

New Insights into Hemopexin-Binding to Hemin and Hemoglobin

New Insights on Hemopexin Binding to Hemin and Hemoglobin

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