title: Hepcidin regulates intrarenal iron handling at the distal nephron.
abstract: Hepcidin, the key regulatory hormone of iron homeostasis, and iron carriers such as transferrin receptor1 (TFR1), divalent metal transporter1 (DMT1), and ferroportin (FPN) are expressed in kidney. Whether hepcidin plays an intrinsic role in the regulation of renal iron transport is unknown. Here, we analyzed the renal handling of iron in hemochromatosis Hepc(-/-) and Hjv(-/-) mouse models, as well as in phenylhydrazine (PHZ)-treated mice. We found a marked medullary iron deposition in the kidneys of Hepc(-/-) mice, and iron leak in the urine. The kidneys of Hepc(-/-) mice exhibited a concomitant decrease in TFR1 and increase in ferritin and FPN expression. Increased FPN abundance was restricted to the thick ascending limb (TAL). DMT1 protein remained unaffected despite a significant decrease of its mRNA level, suggesting that DMT1 protein is stabilized in the absence of hepcidin. Treatment of kidney sections from Hepc(-/-) mice with hepcidin decreased DMT1 protein, an effect confirmed in renal cell lines where hepcidin markedly decreased (55)Fe transport. In the kidneys of Hjv(-/-) mice exhibiting low hepcidin expression, the iron overload was similar to that in the kidneys of Hepc(-/-) mice. However, in PHZ mice, iron accumulation resulting from hemoglobin leak was detected in the proximal tubule. Thus, kidneys exhibit a tissue-specific handling of iron that depends on the extra iron source. Hepcidin may control the expression of iron transporters to prevent renal iron overload.
authors.affiliation: 1] INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, Université Paris Diderot, Site Bichat, Paris, France [2] Université Paris Diderot, Site Bichat, Paris, France.
authors.forename: Boualem
authors.initials: B
authors.lastname: Moulouel
authors.forename: Dounia
authors.initials: D
authors.lastname: Houamel
authors.forename: Constance
authors.initials: C
authors.lastname: Delaby
authors.forename: Dimitri
authors.initials: D
authors.lastname: Tchernitchko
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.forename: Philippe
authors.initials: P
authors.lastname: Letteron
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibaudeau
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000473:pathology; D008138:Loop of Henle / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009893:Opossums; D010659:Phenylhydrazines / Q000009:adverse effects; D011990:Receptors, Transferrin / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D007501:Iron; D008565:Membrane Proteins; D010659:Phenylhydrazines; D011990:Receptors, Transferrin; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C504414:HJV protein, mouse; C480029:Tfrc protein, mouse; C030299:phenylhydrazine