PubMed: 26794659

Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response.
Cell death & disease
Baek JH | Boretti FS | Buehler PW | Deuel JW | Garcia-Rubio I | Opitz L | Schaer CA | Schaer DJ | Spahn DR

Evidence cc977c03c3

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

Evidence 66d1d923fc

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

Evidence cf952afc7c

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

Evidence 44cf790040

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

Evidence 008312453a

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

Evidence 5250c9000c

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.

Evidence a842b2eed2

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).

Evidence 80a2662408

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

Evidence 06ab2a0190

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

Evidence 4315514a7a

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.

Evidence 955859ba05

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.

Evidence 8debf1af40

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.

Evidence 002cd78230

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

Evidence 90abca9486

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

Evidence 2c0b8c4bb1

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

Evidence 38a839cbd4

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

Evidence 9c48c184a2

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).

Evidence d1ebad86f9

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.

Evidence 35af8e32ec

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

Evidence aa9143ecd3

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.

Evidence 0741749746

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.

Evidence ea233b1a22

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

Evidence da8c88544d

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

Evidence 3028e3b326

Hp treatment prevented renal Hb exposure.

Evidence 1f99a0413a

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.

Evidence 25d86f63c5

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

Evidence b54b7d5b65

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

Evidence 629ce9b149

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


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