Abstract
Hemoglobinuria is associated with kidney injury in various hemolytic pathologies. Currently, there is no treatment available and its pathophysiology is not completely understood. Here we studied the potential detrimental effects of hemoglobin (Hb) exposure to the distal nephron (DN). Involvement of the DN in Hb kidney injury was suggested by the induction of renal hepcidin synthesis (p < 0.001) in mice repeatedly injected with intravenous Hb. Moreover, the hepcidin induction was associated with a decline in urinary kidney injury markers 24p3/NGAL and KIM1, suggesting a role for hepcidin in protection against Hb kidney injury. We demonstrated that uptake of Hb in the mouse cortical collecting duct cells (mCCDcl1) is mediated by multi-protein ligand receptor 24p3R, as indicated by a significant 90% reduction in Hb uptake (p < 0.001) after 24p3R silencing. Moreover, incubation of mCCDcl1 cells with Hb or hemin for 4 or 24 h resulted in hepcidin synthesis and increased mRNA expression of markers for oxidative, inflammatory and ER stress, but no cell death as indicated by apoptosis staining. A protective role for cellular hepcidin against Hb-induced injury was demonstrated by aggravation of oxidative, inflammatory and ER stress after 4 h Hb or hemin incubation in hepcidin silenced mCCDcl1 cells. Hepcidin silencing potentiated hemin-mediated cell death that could be diminished by co-incubation of Nec-1, suggesting that endogenous hepcidin prevents necroptosis. Combined, these results demonstrate that renal hepcidin synthesis protects the DN against hemin and hemoglobin-mediated injury.
Highlights
Reactive forms of iron (Fe), such as heme, are increasingly associated with renal injury[1]
L and H-ferritin mRNA expression levels were increased in Hb-treated Hamp silenced cells, but not with hemin incubation. These results demonstrate increased oxidative, inflammatory and endoplasmic reticulum (ER) stress after Hb and hemin exposure in Hamp silenced mCCDcl[1] cells leading to cell death characterized as necroptosis, with more pronounced effects of hemin compared to Hb
Hemoglobinuria is associated with kidney injury in many pathologies involving hemolysis
Summary
Reactive forms of iron (Fe), such as heme, are increasingly associated with renal injury[1]. Hemolysis and subsequent hemoglobinuria have been related to renal injury in various pathologies including paroxysmal nocturnal hemoglobinuria, favism and sickle cell anemia, and as potential post-operative complication of cardiopulmonary bypass[2,3,4,5,6,7]. Hematuria has been linked with hemoglobin-induced kidney injury, e.g., in patients with IgA nephropathy[4]. At this moment, there are no specific. HO-1-mediated catabolism yields intracellular free and reactive Fe2+, which is converted to Fe3+ by H-
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