Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury
Abolfazl Zarjou, … , Lukas C. Kuhn, Anupam Agarwal
Abolfazl Zarjou, … , Lukas C. Kuhn, Anupam Agarwal
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4423-4434. https://doi.org/10.1172/JCI67867.
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Research Article Nephrology

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 (FtHPT–/– mice). FtHPT–/– 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 FtHPT–/– 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 FtHPT–/– 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

Abolfazl Zarjou, Subhashini Bolisetty, Reny Joseph, Amie Traylor, Eugene O. Apostolov, Paolo Arosio, Jozsef Balla, Jill Verlander, Deepak Darshan, Lukas C. Kuhn, Anupam Agarwal

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Figure 4

Increased excretion of urinary iron and iron acceptor proteins in FtHPT–/– mice after AKI.

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Increased excretion of urinary iron and iron acceptor proteins in FtHPT–...
(A) Catalytic iron was measured in the urine of saline- or glycerol-treated FtHPT+/+ and FtHPT–/– mice. Data were normalized to urine creatinine levels and expressed as nanomoles of iron per milligram creatinine. *P < 0.05 vs. respective saline control. (B) Total iron content was measured in the urine of glycerol-treated FtHPT+/+ and FtHPT–/– mice. Data were normalized to urine creatinine and expressed as microgram iron per milligram creatinine. (C and D) Hemopexin, NGAL, and transferrin were measured by ELISA in the urine from glycerol- (C) or cisplatin-treated (D) FtHPT+/+ and FtHPT–/– mice. Data were normalized to urine creatinine and expressed as microgram per milligram creatinine. *P < 0.05 vs. FtHPT+/+.