Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome.

Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic , primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by ) in HUS has not yet been investigated. We hypothesized that HO-1 also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced gene deletion (Hmox1) and control mice (Hmox1). This HO-1 induction was significantly lower (-43%) in Hmox1 mice compared to Hmox1 mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase ( = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase ( = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS.