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• W4205513426 endingPage "1185" @default.
• W4205513426 startingPage "1171" @default.
• W4205513426 abstract "Thrombotic microangiopathy, hemolysis and acute kidney injury are typical clinical characteristics of hemolytic-uremic syndrome (HUS), which is predominantly caused by Shiga-toxin-producing Escherichia coli. Free heme aggravates organ damage in life-threatening infections, even with a low degree of systemic hemolysis. Therefore, we hypothesized that the presence of the hemoglobin- and the heme-scavenging proteins, haptoglobin and hemopexin, respectively impacts outcome and kidney pathology in HUS. Here, we investigated the effect of haptoglobin and hemopexin deficiency (haptoglobin-/-, hemopexin-/-) and haptoglobin treatment in a murine model of HUS-like disease. Seven-day survival was decreased in haptoglobin-/- (25%) compared to wild type mice (71.4%), whereas all hemopexin-/- mice survived. Shiga-toxin-challenged hemopexin-/- mice showed decreased kidney inflammation and attenuated thrombotic microangiopathy, indicated by reduced neutrophil recruitment and platelet deposition. These observations were associated with supranormal haptoglobin plasma levels in hemopexin-/- mice. Low dose haptoglobin administration to Shiga-toxin-challenged wild type mice attenuated kidney platelet deposition and neutrophil recruitment, suggesting that haptoglobin at least partially contributes to the beneficial effects. Surrogate parameters of hemolysis were elevated in Shiga-toxin-challenged wild type and haptoglobin-/- mice, while signs for hepatic hemoglobin degradation like heme oxygenase-1, ferritin and CD163 expression were only increased in Shiga-toxin-challenged wild type mice. In line with this observation, haptoglobin-/- mice displayed tubular iron deposition as an indicator for kidney hemoglobin degradation. Thus, haptoglobin and hemopexin deficiency plays divergent roles in Shiga-toxin-mediated HUS, suggesting haptoglobin is involved and hemopexin is redundant for the resolution of HUS pathology." @default.
• W4205513426 created "2022-01-26" @default.
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• W4205513426 date "2022-06-01" @default.
• W4205513426 modified "2023-10-18" @default.
• W4205513426 title "Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin–induced hemolytic-uremic syndrome in mice" @default.
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• W4205513426 doi "https://doi.org/10.1016/j.kint.2021.12.024" @default.
• W4205513426 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35031328" @default.
• W4205513426 hasPublicationYear "2022" @default.
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