title: Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury.
abstract: Ferritin plays a central role in iron metabolism and is made of 24 subunits of 2 types: heavy chain and light chain. The ferritin heavy chain (FtH) has ferroxidase activity that is required for iron incorporation and limiting toxicity. The purpose of this study was to investigate the role of FtH in acute kidney injury (AKI) and renal iron handling by using proximal tubule-specific FtH-knockout mice (FtH(PT-/-) mice). FtH(PT-/-) mice had significant mortality, worse structural and functional renal injury, and increased levels of apoptosis in rhabdomyolysis and cisplatin-induced AKI, despite significantly higher expression of heme oxygenase-1, an antioxidant and cytoprotective enzyme. While expression of divalent metal transporter-1 was unaffected, expression of ferroportin (FPN) was significantly lower under both basal and rhabdomyolysis-induced AKI in FtH(PT-/-) mice. Apical localization of FPN was disrupted after AKI to a diffuse cytosolic and basolateral pattern. FtH, regardless of iron content and ferroxidase activity, induced FPN. Interestingly, urinary levels of the iron acceptor proteins neutrophil gelatinase-associated lipocalin, hemopexin, and transferrin were increased in FtH(PT-/-) mice after AKI. These results underscore the protective role of FtH and reveal the critical role of proximal tubule FtH in iron trafficking in AKI.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Zarjou
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.forename: Reny
authors.initials: R
authors.lastname: Joseph
authors.forename: Amie
authors.initials: A
authors.lastname: Traylor
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Apostolov
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.forename: Jozsef
authors.initials: J
authors.lastname: Balla
authors.forename: Jill
authors.initials: J
authors.lastname: Verlander
authors.forename: Deepak
authors.initials: D
authors.lastname: Darshan
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Kuhn
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D001052:Apoferritins / Q000378:metabolism*; D001483:Base Sequence; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation; D060005:Genotyping Techniques; D007501:Iron / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012206:Rhabdomyolysis / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D001052:Apoferritins; D027682:Cation Transport Proteins; D017931:DNA Primers; D007501:Iron; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
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