title: Prion protein promotes kidney iron uptake via its ferrireductase activity.
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.
authors.affiliation: From the Departments of Pathology and.
authors.forename: Swati
authors.initials: S
authors.lastname: Haldar
authors.affiliation: From the Departments of Pathology and.
authors.forename: Ajai
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: From the Departments of Pathology and.
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.affiliation: From the Departments of Pathology and.
authors.forename: Amber
authors.initials: A
authors.lastname: Beserra
authors.affiliation: From the Departments of Pathology and.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Suda
authors.affiliation: From the Departments of Pathology and.
authors.forename: Matthew
authors.initials: M
authors.lastname: McElwee
authors.affiliation: the Department of Pathology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Jerrold
authors.initials: J
authors.lastname: Turner
authors.affiliation: Physiology and Biophysics, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio 44106 and.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hopfer
authors.affiliation: From the Departments of Pathology and neena.singh@case.edu.
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D038181:FMN Reductase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017136:Ion Transport / Q000235:genetics; D007501:Iron / Q000378:metabolism* / Q000493:pharmacokinetics; D007504:Iron Radioisotopes; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D007504:Iron Radioisotopes; D018621:PrPC Proteins; D014168:Transferrin; D007501:Iron; D038181:FMN Reductase; C023903:ferric citrate iron reductase
keywords: Aggregation; Iron Metabolism; Kidney; Kidney Iron Metabolism; Metal Homeostasis; NTBI; Prion Disease