Abstract
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 PrP(C) in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrP(C) is lacking. Kidney provides a relevant model for this evaluation because PrP(C) 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 (59)Fe 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 (59)Fe revealed similar results. Expression of exogenous PrP(C) in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of (59)Fe-NTBI and to a smaller extent (59)Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductase-deficient mutant of PrP (PrP(Δ51-89)) 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.
Highlights
Primarily a neuronal protein, prion protein (PrPC) is expressed in the kidney, suggesting a functional role
We evaluated the role of PrPC in iron uptake by the kidney in transgenic mouse models lacking PrP (PrPϪ/Ϫ) [23] and immortalized mouse PT cells that differentiate in culture to form functional monolayers with tight junctions [24]
Absence of PrPC Reduces Iron Uptake by the Kidney—Ageand sex-matched PrPϩ/ϩ and PrPϪ/Ϫ mice were exposed to radiolabeled iron (59Fe-citrate) by gavage feeding and intravenous (IV) or intra-peritoneal (IP) route, and uptake of 59Fe by the kidney was quantified in a ␥-counter (Fig. 1, A–C). 59Fecitrate introduced by gavage feeding is expected to radiolabel mainly plasma Tf, whereas injection by the intravenous and intraperitoneal routes is likely to radiolabel both Tf and non-Tf-bound iron (NTBI) but preferentially Tf because of its high affinity for iron
Summary
Primarily a neuronal protein, prion protein (PrPC) is expressed in the kidney, suggesting a functional role. Excess NTBI and hemin caused aggregation of PrPC to a detergent-insoluble form, limiting iron uptake Together, these observations suggest that PrPC promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism. The presence of PrPC in the urine of healthy individuals suggests that it is expressed on PT cells where it may provide FR activity necessary for the uptake of Tf-iron and NTBI [4, 5, 17] To explore this possibility, we evaluated the role of PrPC in iron uptake by the kidney in transgenic mouse models lacking PrP (PrPϪ/Ϫ) [23] and immortalized mouse PT cells that differentiate in culture to form functional monolayers with tight junctions [24]. Excess NTBI and hemin aggregate PrPC to a detergent-insoluble form, preventing further iron uptake
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