Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity.
The kidney has recently emerged as an organ with a significant role in systemic iron (Fe) homeostasis. Substantial amounts of Fe are filtered by the kidney, which have to be reabsorbed to prevent Fe deficiency. Accordingly Fe transporters and receptors for protein-bound Fe are expressed in the nephron that may also function as entry pathways for toxic metals, such as cadmium (Cd), by way of "ionic and molecular mimicry". Similarities, but also differences in handling of Cd by these transport routes offer rationales for the propensity of the kidney to develop Cd toxicity. This critical review provides a comprehensive update on Fe transport by the kidney and its relevance for physiology and Cd nephrotoxicity. Based on quantitative considerations, we have also estimated the in vivo relevance of the described transport pathways for physiology and toxicology. Under physiological conditions all segments of the kidney tubules are likely to utilize Fe for cellular Fe requiring processes for metabolic purposes and also to contribute to reabsorption of free and bound forms of Fe into the circulation. But Cd entering tubule cells disrupts metabolic pathways and is unable to exit. Furthermore, our quantitative analyses contest established models linking chronic Cd nephrotoxicity to proximal tubular uptake of metallothionein-bound Cd. Hence, Fe transport by the kidney may be beneficial by preventing losses from the body. But increased uptake of Fe or Cd that cannot exit tubule cells may lead to kidney injury, and Fe deficiency may facilitate renal Cd uptake.
Institute of Physiology, Pathophysiology & Toxicology, Center for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, Stockumer Str. 12, 58453 Witten, Germany. frank.thevenod@uni-wh.de natascha.wolff@uni-wh.de.
Frank
F
Thévenod
Institute of Physiology, Pathophysiology & Toxicology, Center for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, Stockumer Str. 12, 58453 Witten, Germany. frank.thevenod@uni-wh.de natascha.wolff@uni-wh.de.
Natascha A
NA
Wolff
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000378:metabolism
D026901:Membrane Transport Proteins; D002104:Cadmium; D007501:Iron