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The liver hormone hepcidin regulates systemic iron homeostasis. Hepcidin is also expressed by the kidney, but exclusively in distal nephron segments. Several studies suggest hepcidin protects against kidney damage involving Fe 2+ overload. The nephrotoxic non-essential metal ion Cd 2+ can displace Fe 2+ from cellular biomolecules, causing oxidative stress and cell death. The role of hepcidin in Fe 2+ and Cd 2+ toxicity was assessed in mouse renal cortical [mCCD(cl.1)] and inner medullary [mIMCD 3 ] collecting duct cell lines. Cells were exposed to equipotent Cd 2+ (0.5-5 μmol/l) and/or Fe 2+ (50-100 μmol/l) for 4-24 h. Hepcidin (Hamp1) was transiently silenced by RNAi or overexpressed by plasmid transfection. Hepcidin or catalase expression were evaluated by RT-PCR, qPCR, immunoblotting or immunofluorescence microscopy, and cell fate by MTT, apoptosis and necrosis assays. Reactive oxygen species (ROS) were detected using CellROX™ Green and catalase activity by fluorometry. Hepcidin upregulation protected against Fe 2+ -induced mIMCD 3 cell death by increasing catalase activity and reducing ROS, but exacerbated Cd 2+ -induced catalase dysfunction, increasing ROS and cell death. Opposite effects were observed with Hamp1 siRNA. Similar to Hamp1 silencing, increased intracellular Fe 2+ prevented Cd 2+ damage, ROS formation and catalase disruption whereas chelation of intracellular Fe 2+ with desferrioxamine augmented Cd 2+ damage, corresponding to hepcidin upregulation. Comparable effects were observed in mCCD(cl.1) cells, indicating equivalent functions of renal hepcidin in different collecting duct segments. In conclusion, hepcidin likely binds Fe 2+ , but not Cd 2+ . Because Fe 2+ and Cd 2+ compete for functional binding sites in proteins, hepcidin affects their free metal ion pools and differentially impacts downstream processes and cell fate.

archives of toxicology

Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium