Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

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 (AM) and renal iron handling by using proximal tubule-specific FtH-knockout mice (FtHPT(-/-) mice). FtHPT(-/-) mice had significant mortality, worse structural and functional renal injury, and increased levels of apoptosis in rhabdomyolysis and cisplatin-induced AM, 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 rhabd.omyolysis-induced AM in FtHPT(-/-) mice. Apical localization of FPN was disrupted after AM to a diffuse cytosolic and basolateral pattern. FtH, regardless ofiron content and ferroxidase activity, induced FPN. Interestingly, urinary levels of the iron acceptor proteins neutrophil gelatihase-associated lipocalin, hemopexin, and transferrin were increased in FtHPT(-/-) mice after AM. These results underscore the protective role of FtH and reveal the critical role of proximal tubule FtH in iron trafficking in AM.