|Ph.D Student||Weiss Avital|
|Subject||Mechanism and Regulation of Iron Trafficking through the|
|Department||Department of Biotechnology and Food Engineering||Supervisor||Dr. Esther Meyron Holtz|
Systemic iron homeostasis is determined by iron uptake and iron loss and it is well accepted that no iron is lost in urine. The basic functional unit of the kidney is the nephron, which extends from the cortex to the medulla, allowing blood plasma filtration and protein re-absorption. Recent reports claim that transferrin is filtered into primary urine and that it is reabsorbed through receptor mediated endocytosis either by transferrin-receptor-1 (TfR1) or by the multiligand receptor cubilin. Iron metabolism proteins, such as DMT1, ferroportin (FPN), ferritin, and the iron regulatory proteins are all expressed in proximal tubule cells, which are a major site for nutrient re-absorption in the kidney. Here we examined expression-levels and localization of proteins that may be involved in kidney iron reabsorption, to elucidate how the kidney reabsorbs iron. We hypothesized that iron transport proteins in the kidney may be regulated in a tissue specific manner, especially in response to iron overload.
In iron overloaded mice, accumulation of iron was detected mainly in the medulla and immuno-fluorescent (IF) staining showed that TfR1 was localized apically mainly in the medulla of iron overloaded and control kidneys. Interestingly, by Western blot analysis, cubilin was showing increased expression, which was confirmed by IF, showing cubilin expression not only in the cortex but also in the medulla. High ferritin and FPN protein expression was detected by Western blot analysis. Ferritin was localized by IF and IHC in both the cortex and medulla, not only intra-tubular but also in the interstitium and partly correlated with macrophages in the medulla. In response to the iron load, elevated levels of heme-oxygenase and the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α), were detected by Western blot and quantitative PCR respectively.
These results suggest a model in which during iron overload, renal cellular regulation functions in an attempt to scavenge all filtered iron, without releasing it to the urine. This occurs through a unique regulation of the iron-transporters in the kidney and cooperation between cortical and medullar regions of the nephron. Nevertheless, kidney epithelial cells are protected from the iron load, probably by excretion of iron through FPN (and perhaps secretion of ferritin). The iron released, accumulates at least in part, in macrophages in the interstitium, which might promote inflammation. Cubilin overexpression might result in the reabsorption of antibiotics and toxins, which can further exacerbate inflammation and conditions that predispose to development of renal cancer.