Altered dietary iron intake is a strong modulator of renal DMT1 expression

Abstract

Divalent metal transporter1 (DMT1; also known as DCT1 or NRAMP2) is an important component of the cellular machinery responsible for dietary iron absorption in the duodenum. DMT1 is also highly expressed in the kidney where it has been suggested to play a role in urinary iron handling. In this study, we determined the effect on renal DMT1 expression of feeding an iron-restricted diet (50 mg/kg) or an iron-enriched diet (5 g/kg) for 4 wk and measured urinary and fecal iron excretion rates. Feeding the low-iron diet caused a reduction in serum iron concentration and fecal iron output rate with an increase in renal DMT1 expression. Feeding an ironenriched diet had the converse effect. Therefore, DMT1 expression in the kidney is sensitive to dietary iron intake, and the level of expression is inversely related to the dietary iron content. Changes in DMT1 expression occurred intracellularly in the proximal tubule and in the apical membrane and subapical region of the distal convoluted tubule. Increased DMT1 expression was accompanied by a decrease in urinary iron excretion rate and vice versa when DMT1 expression was reduced. Together, these findings suggest that modulation of renal DMT1 expression may influence renal iron excretion rate. serum iron level; kidney; iron regulatory protein; SLC11A2; NRAMP2 IRON IS AN ESSENTIAL metal for life because it is a key constituent of a family of fundamental proteins, which includes hemoglobin, cytochromes, and NADH-coenzyme Q reductase. Maintaining the correct balance of iron is paramount to health because iron deficiency or excess results in morbidity and mortality. The molecular characterization of membrane-bound iron transporter proteins, in particular divalent metal transporter1 (DMT1; 9), also known as DCT1 (14) or NRAMP2 (13), has shed new light on some of the mechanisms of body iron homeostasis. DMT1 is the product of the

Role of the kidney in iron homeostasis: renal expression of Prohepcidin, Ferroportin, and DMT1 in anemic mice

“…Renal DMT1 is another iron protein that to date has not been studied in depth in hemolytic anemia. Our results showing intense DMT1 expression in medulla in anemia are in agreement with those reported in animals on an iron-restricted diet, a condition of increased iron demand (33). The DMT1 expression observed in inner and outer medulla in healthy mice is similar to that reported by other authors (10,13).…”

“…High levels of dietary iron produce an increase in DMT1 expression in hepatocytes, promoting iron acquisition, whereas low levels decrease hepatic DMT1 expression, causing a reduction in iron accumulation (26,32). Although kidney is not usually associated with serum iron balance, several studies found renal DMT1 expression in mice and rats, suggesting that this organ may have a role in iron homeostasis (4,10,33). Furthermore, Wareing et al (34) reported a decrease in urinary iron levels, suggesting iron reabsorption in renal tubules.…”

Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo

“…Interestingly, four DMT1 isoforms have been identified in renal tissue (19). Thus the difference between the effects of Zn 2ϩ action on Cd 2ϩ uptake in the LH and more distal segments could be due to the pattern of expression of these different isoforms (33).…”

Manganese neurotoxicity: A focus on the neonate

“…The existence of the mutated DMT1 molecule in neurons suggests that the low cerebral iron uptake in b/b rats derives from a reduced neuronal uptake rather than an impaired iron transport through the blood-brain barrier (Moos & Morgan, 2004). Kidney studies remain to show the importance of DMT1 as well as different isoforms (Abouhamed et al, 2006;Canonne-Hergaux & Gros, 2002;Wareing et al, 2003;. Pharmacokinetic studies show that iron status can alter lung Mn transport to circulation Heilig et al, 2005;Thompson et al, 2006) DMT1 is not the transporter involved .…”