Hepcidin, an
iron regulatory
peptide, plays a central role in the maintenance of systemic
iron homeostasis by inducing the internalization and degradation of the
iron exporter,
ferroportin.
Hepcidin expression in the liver is regulated in response to several stimuli including
iron status, erythropoietic activity,
hypoxia and
inflammation.
Hepcidin expression has been shown to be reduced in
phenylhydrazine-treated mice, a mouse model of acute
hemolysis. In this mouse model,
hepcidin suppression was associated with increased expression of molecules involved in
iron transport and recycling. The present study aims to explore whether the response to
phenylhydrazine treatment is affected by
hepcidin deficiency and/or the subsequently altered
iron metabolism. Hepcidin1 knockout (Hamp(-/-)) and wild type mice were treated with
phenylhydrazine or saline and parameters of
iron homeostasis were determined 3 days after the treatment. In wild type mice,
phenylhydrazine administration resulted in significantly reduced serum
iron, increased tissue non-
heme iron levels and suppressed
hepcidin expression. The treatment was also associated with increases in membrane
ferroportin protein levels and spleen
heme oxygenase 1 mRNA expression. In addition, trends toward increased
mRNA expression of duodenal
iron transporters were also observed. In contrast, serum
iron and tissue non-
heme iron levels in Hamp(-/-) mice were unaffected by the treatment. Moreover, the effects of
phenylhydrazine on the expression of
ferroportin and duodenal
iron transporters were not observed in Hamp(-/-) mice. Interestingly,
mRNA levels of molecules involved in splenic
heme uptake and degradation were significantly induced by Hamp disruption. In summary, our study demonstrates that the response to
phenylhydrazine-induced
hemolysis differs between wild type and Hamp(-/-) mice. This observation may be caused by the absence of
hepcidin per se or the altered
iron homeostasis induced by the lack of
hepcidin in these mice.