Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin-induced hemolytic-uremic syndrome in mice

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.

Automated summary

Thrombotic microangiopathy, hemolysis and acute kidney injury are typical characteristics of HUS. This study investigated the impact of haptoglobin and hemopexin on HUS. The results showed that haptoglobin deficiency decreased survival rate, while hemopexin deficiency reduced kidney inflammation and thrombotic microangiopathy. Low dose haptoglobin administration attenuated kidney damage. Signs of kidney hemoglobin degradation were observed in HUS.