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PubMed: 26794659

Title
Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response.
Journal
Cell death & disease
Volume
7
Issue
None
Pages
e2064
Date
2016-01-21
Authors
Baek JH | Boretti FS | Buehler PW | Deuel JW | Garcia-Rubio I | Opitz L | Schaer CA | Schaer DJ | Spahn DR

Evidence cc977c03c3
JSON

Renal tissues from old blood-transfused animals exhibited 4-HNE-positive staining.

a(CHEBI:"4-hydroxynon-2-enal") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"4-hydroxynon-2-enal") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 66d1d923fc
JSON

In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively.

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

p(HGNC:HBB) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

Evidence cf952afc7c
JSON

This ATP depletion was prevented by the addition of the heme scavenger, hemopexin (Figure 5b).

a(CHEBI:ATP) positiveCorrelation p(HGNC:HPX) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

p(HGNC:HPX) positiveCorrelation a(CHEBI:ATP) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 44cf790040
JSON

Reduced glutathione (GSH) was also depleted after 4 h of heme exposure, indicating that heme induces oxidative stress in exposed cells (Figure 5c).

a(CHEBI:glutathione) negativeCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) decreases a(CHEBI:glutathione) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

bp(MESH:"Oxidative Stress") negativeCorrelation a(CHEBI:glutathione) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 008312453a
JSON

Free heme is a potent trigger of lipid peroxidation and a promoter of inflammation.4–6

a(CHEBI:heme) positiveCorrelation bp(MESH:"Lipid Peroxidation") View Subject | View Object

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Annotations
Text Location
Introduction

a(CHEBI:heme) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Text Location
Introduction

bp(MESH:"Lipid Peroxidation") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
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Text Location
Introduction

path(MESH:Inflammation) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Text Location
Introduction

Evidence 5250c9000c
JSON

The above-discussed findings provide strong in vivo evidence that high concentrations of ferric Hb(Fe3+) and free heme can accumulate in the renal cortex during hemolysis.

a(CHEBI:heme) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Cortex
Text Location
Discussion

a(CHEBI:methemoglobin) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Cortex
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Cortex
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation a(CHEBI:methemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Cortex
Text Location
Discussion

Evidence a842b2eed2
JSON

In agreement with the electrical cell–substrate impedance sensing data described above, the proteome changes triggered by 10 μM heme were indicative of an adaptive response with prominent induction of HMOX1 and ferritin light (FTL) and heavy (FTH1) chains (Figure 5d,left panel).

a(CHEBI:heme) increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:FTL) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:FTH1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 80a2662408
JSON

Other studies demonstrated that heme can trigger the activation of Toll-like receptor 4 and inflammasomes, thus leading to inflammatory reactions.5,35–37

a(CHEBI:heme) positiveCorrelation p(HGNC:TLR4) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

bp(GO:"inflammatory response") positiveCorrelation p(HGNC:TLR4) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

p(HGNC:TLR4) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

p(HGNC:TLR4) positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

Evidence 06ab2a0190
JSON

At high concentrations, heme can act as an endogenous inhibitor of the proteasome and as a trigger of the response to unfolded proteins in vitro.7

a(CHEBI:heme) decreases p(PFAM:Proteasome) View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

Evidence 4315514a7a
JSON

These data suggest that the estimated free heme concentrations that occur in the renal tubular system during severe intravascular hemolysis are in the range of heme concentrations that could trigger oxidative stress and cell damage to the renal epithelium.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 955859ba05
JSON

Accordingly, heme exposures of more than 10 μM caused the significant and progressive depletion of cellular ATP, which was measured after an 8-h exposure period.

a(CHEBI:heme) decreases a(CHEBI:ATP) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 8debf1af40
JSON

However, in the presence of 40 μM heme, the toxic response was characterized by the strong induction of heat shock proteins, namely HSP70 (HSPA1B, HSPA4, HSPA5, DNAJB1), HSP72 (HSPA1A), HSP105 (HSPH1), and HSP10 (HSPE1), as well as the proteasome adaptor protein sequestosome.

a(CHEBI:heme) increases p(HGNC:HSPA1B) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:HSPA4) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:HSPA5) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:DNAJB1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:HSPA1A) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:HSPH1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(CHEBI:heme) increases p(HGNC:HSPE1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 002cd78230
JSON

In the presence of both 10 and 40 μM, the transferrin receptor was identified as the most suppressed protein.

a(CHEBI:heme) decreases p(HGNC:TFRC) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 90abca9486
JSON

The ratio of spliced XBP1 to either total XBP1 or unspliced XBP1 was strongly increased by 40 μM heme for 4 and 8 h.

a(CHEBI:heme) increases p(HGNC:XBP1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence 2c0b8c4bb1
JSON

Ultimately, we found that uncontrolled cellular heme levels can activate the response to unfolded proteins and associated apoptosis pathways in mouse embryonic fibroblast cells.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Unfolded Protein Response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

bp(MESH:"Unfolded Protein Response") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

Evidence 38a839cbd4
JSON

However, at higher heme concentrations (20 and 40 μM), we observed a cytotoxic response with the irreversible breakdown of the epithelial barrier.

a(CHEBI:heme) negativeCorrelation a(MESH:"Glomerular Filtration Barrier") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Cortex
Text Location
Discussion

a(MESH:"Glomerular Filtration Barrier") negativeCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Cortex
Text Location
Discussion

Evidence 9c48c184a2
JSON

Electron paramagnetic resonance (EPR) spectra of renal tissues from old blood-transfused animals were recorded at 6K and showed a strong signal around g=6, which is indicative of high-spin ferric Hb(Fe3+) (Figure 3a).

a(CHEBI:methemoglobin) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:methemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence d1ebad86f9
JSON

First, quantification of high-spin ferric Hb(Fe3+), which is the initial Hb oxidation product resulting from the oxidation of ferrous oxyHb(Fe2+), in the kidneys of the old blood-transfused guinea pigs suggests very high concentrations of ferric Hb can accumulate in renal tissues at 24 h after old blood transfusion.

a(CHEBI:methemoglobin) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:methemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Discussion

Evidence 35af8e32ec
JSON

No high-spin ferric Hb was present in the control tissues or renal tissues of old blood-transfused, Hp-treated guinea pigs.

a(CHEBI:methemoglobin) negativeCorrelation p(HGNC:HP) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

p(HGNC:HP) negativeCorrelation a(CHEBI:methemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence aa9143ecd3
JSON

Isovolemic transfusion of guinea pigs with 10-unit equivalents of old blood, which consisted of red blood cells that were stored for 28 days, led to moderate hemoglobinuria.

a(MESH:"Blood Transfusion") positiveCorrelation path(MESH:Hemoglobinuria) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Results

path(MESH:Hemoglobinuria) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Results

Evidence 0741749746
JSON

Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h.

a(MESH:"Blood Transfusion") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Results

a(MESH:Kidney) negativeCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Results

p(HGNC:HBB) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Results

p(HGNC:HBB) negativeCorrelation a(MESH:Kidney) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Results

Evidence ea233b1a22
JSON

Immunofluorescence confirmed that renal Hb exposure triggered overexpression of HMOX1 and the unfolded protein response (UPR) chaperone HSP70 in tubule epithelial cells (Figure 2d).

p(HGNC:HBB) increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

p(HGNC:HBB) increases p(HGNC:HSPA5) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence da8c88544d
JSON

Free Hb is bound by the plasma protein haptoglobin, and the large molecular size Hb: Hp complexes are ultimately cleared by spleen and liver macrophages expressing the Hb scavenger receptor CD163.8

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Introduction

Evidence 3028e3b326
JSON

Hp treatment prevented renal Hb exposure.

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

Evidence 1f99a0413a
JSON

The prevention of renal Hb filtration by Hp may be a therapeutic strategy to block renal Hb exposure and to rescue renal function in patients with severe hemoglobinuria.

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
MeSH
Hemoglobinuria
Text Location
Discussion

Evidence 25d86f63c5
JSON

In control, new blood-transfused, and old bloodtransfused, Hp-treated animals, 4-HNE was not detected.

p(HGNC:HP) decreases a(CHEBI:"4-hydroxynon-2-enal") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
Text Location
Results

Evidence b54b7d5b65
JSON

Therefore, acute kidney injury (AKI) remains an important complication of acute and severe intravascular hemolysis.

path(MESH:"Acute Kidney Injury") positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation path(MESH:"Acute Kidney Injury") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Introduction

Evidence 629ce9b149
JSON

Renal damage has also been reported to occur throughout many other acute hemolytic conditions associated with hemoglobinuria.

path(MESH:"Acute Kidney Injury") association path(MESH:Hemoglobinuria) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Introduction

path(MESH:Hemoglobinuria) association path(MESH:"Acute Kidney Injury") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
Text Location
Introduction

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