Prion protein promotes kidney iron uptake via its ferrireductase activity

Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrP^C) from its normal conformation to an aggregated, PrP-scrapie (PrP^Sc) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrPN^C in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrPC is lacking. Kidney provides a relevant model for this evaluation because PrPC is expressed in the kidney, and ∼370 μg of iron are reabsorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrP^C promotes the uptake of transferrin (Tf) and non-Tf-bound iron (NTBI) by the kidney in vivo and mainly NTBI by PT cells in vitro. Thus, uptake of ⁵⁹Fe administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP^-/-) mouse kidney relative to PrP^+/+ controls. Selective in vivo radiolabeling of plasma NTBI with ⁵⁹Fe revealed similar results. Expression of exogenous PrPC in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of ⁵⁹Fe-NTBI and to a smaller extent ⁵⁹Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductasedeficient mutant of PrP (PrPΔ51-89) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrP^C to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrP^C promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism.