Erythropoietin regulates intestinal iron absorption in a rat model of chronic renal failure

• Published in: Kidney international Vol. 78; no. 7; pp. 660 - 667
• Main Authors: Srai, Surjit K., Chung, Bomee, Marks, Joanne, Pourvali, Katayoun, Solanky, Nita, Rapisarda, Chiara, Chaston, Timothy B., Hanif, Rumeza, Unwin, Robert J., Debnam, Edward S., Sharp, Paul A.
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.10.2010; Nature Publishing Group; Elsevier Limited
• Subjects: Animals; Antimicrobial Cationic Peptides - genetics; Biological and medical sciences; Caco-2 Cells; Cation Transport Proteins - genetics; Disease Models, Animal; duodenum; Duodenum - metabolism; enterocyte; erythropoietin; Erythropoietin - pharmacology; hepcidin; Hepcidins; Humans; Intestinal Absorption - drug effects; iron; Iron - metabolism; Kidney Failure, Chronic - metabolism; Male; Medical sciences; Nephrectomy; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin - analysis; Renal failure; RNA, Messenger - analysis; Signal Transduction; iron; hepcidin; enterocyte; duodenum; erythropoietin; Kidney disease; Animal model; Nephrology; Urinary system disease; Chronic renal failure; Duodenum; Erythropoietin; Rat; Digestive system; Rodentia; Iron; Small intestine; Urology; Vertebrata; Regulation(control); Mammalia; Polypeptide; Enterocyte; Intestinal absorption; Hepcidin
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2010.217

Erythropoietin is produced by the kidney and stimulates erythropoiesis; however, in chronic renal disease its levels are reduced and patients develop anemia that is treatable with iron and recombinant hormone. The mechanism by which erythropoietin improves iron homeostasis is still unclear, but it may involve suppression of the iron regulatory peptide hepcidin and/or a direct effect on intestinal iron absorption. To investigate these possibilities, we used the well-established 5/6th nephrectomy rat model of chronic renal failure with or without human recombinant erythropoietin treatment. Monolayers of human intestinal Caco-2 cells were also treated with erythropoietin to measure any direct effects of this hormone on intestinal iron transport. Nephrectomy increased hepatic hepcidin expression and decreased intestinal iron absorption; these effects were restored to levels found in sham-operated rats on erythropoietin treatment of the rats with renal failure. In Caco-2 cells, the addition of erythropoietin significantly increased the expression of apical divalent metal transporter 1 (DMT1) and basolateral ferroportin and, consequently, iron transport across the monolayer. Taken together, our results show that erythropoietin not only exerts a powerful inhibitory action on the expression of hepcidin, thus permitting the release of iron from reticuloendothelial macrophages and intestinal enterocytes, but also acts directly on enterocytes to increase iron absorption.