Abstract
Iron overload damages many organs. Unfortunately, therapeutic iron chelators also have undesired toxicity and may deliver iron to microbes. Here we show that a mutant form (K3Cys) of endogenous lipocalin 2 (LCN2) is filtered by the kidney but can bypass sites of megalin-dependent recapture, resulting in urinary excretion. Because K3Cys maintains recognition of its cognate ligand, the iron siderophore enterochelin, this protein can capture and transport iron even in the acidic conditions of urine. Mutant LCN2 strips iron from transferrin and citrate, and delivers it into the urine. In addition, it removes iron from iron overloaded mice, including models of acquired (iron-dextran or stored red blood cells) and primary (Hfe−/−) iron overload. In each case, the mutants reduce redox activity typical of non-transferrin-bound iron. In summary, we present a non-toxic strategy for iron chelation and urinary elimination, based on manipulating an endogenous protein:siderophore:iron clearance pathway.
Highlights
We show that a mutant form (K3Cys) of endogenous lipocalin 2 (LCN2) is filtered by the kidney but can bypass sites of megalin-dependent recapture, resulting in urinary excretion
Disruption of iron regulation can produce primary, secondary and acquired iron overload disorders. These disorders are characterized by elevated transferrin saturation (450%), high levels of circulating ferritin (41,000 mg l À 1)[1,2,3], the emergence of ‘non-transferrinbound iron’ (NTBI) associated with proteins and small organic molecules (NTBI: 0.9–12.8 mmol l À 1 in thalassemic and 4–16.3 mM in hereditary haemochromatosis sera2), and increases in the cellular labile iron pool (LIP)[4]
The capture of LCN2 from the glomerular filtrate is thought to be mediated by megalin, a multi-ligand endocytic receptor positioned at the luminal surface of lotus þ proximal tubules (Fig. 1a)[36]
Summary
Generation of LCN2 mutants that can bypass renal reabsorption. The capture of LCN2 from the glomerular filtrate is thought to be mediated by megalin, a multi-ligand endocytic receptor positioned at the luminal surface of lotus þ proximal tubules (Fig. 1a)[36]. Negligible amounts of protein and iron (0.06%) were excreted into the urine by native LCN2, despite adequate loading with Ent:55Fe (Supplementary Fig. 2b). Inoculation of iron citrate resulted in the urinary excretion of only 1.9±2%, but the subsequent inoculation of 25 nmoles K3Cys:Ent resulted in the excretion of 24±8% of iron (P 1⁄4 0.0019, Student’s t-test; n 1⁄4 5; Supplementary Fig. 4d). These data were striking because neither Tf-55Fe nor Citrate-55Fe alone could label the kidney[27]. K3Cys:Ent can capture and transfer iron into the urine from either exogenous Tf or Citrate
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