Hepcidin regulates intrarenal iron handling at the distal nephron
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...
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Veröffentlicht in: | Kidney international 2013-10, Vol.84 (4), p.756-766 |
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creator | Moulouel, Boualem Houamel, Dounia Delaby, Constance Tchernitchko, Dimitri Vaulont, Sophie Letteron, Philippe Thibaudeau, Olivier Puy, Hervé Gouya, Laurent Beaumont, Carole Karim, Zoubida |
description | 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 55Fe 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. |
doi_str_mv | 10.1038/ki.2013.142 |
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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 55Fe 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.</description><identifier>ISSN: 0085-2538</identifier><identifier>EISSN: 1523-1755</identifier><identifier>DOI: 10.1038/ki.2013.142</identifier><identifier>PMID: 23615502</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cation Transport Proteins - metabolism ; Cell Line ; Cells, Cultured ; Disease Models, Animal ; Hemochromatosis - chemically induced ; Hemochromatosis - genetics ; Hemochromatosis - metabolism ; Hepcidins - deficiency ; Hepcidins - genetics ; Hepcidins - metabolism ; Homeostasis - physiology ; In Vitro Techniques ; ion transport ; Iron - metabolism ; kidney tubule ; Kidney Tubules, Distal - metabolism ; Kidney Tubules, Distal - pathology ; Loop of Henle - metabolism ; Membrane Proteins - deficiency ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mice, Knockout ; mineral metabolism ; Opossums ; pathology ; Phenylhydrazines - adverse effects ; Receptors, Transferrin - metabolism ; renal epithelial cell</subject><ispartof>Kidney international, 2013-10, Vol.84 (4), p.756-766</ispartof><rights>2013 International Society of Nephrology</rights><rights>Copyright Nature Publishing Group Oct 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-77fae6c9d86f0524b2aff18de68f4205caaa59e8af4302cc7e5b767757ef34963</citedby><cites>FETCH-LOGICAL-c400t-77fae6c9d86f0524b2aff18de68f4205caaa59e8af4302cc7e5b767757ef34963</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1437629629?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>315,781,785,27929,27930,64390,64392,64394,72474</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23615502$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moulouel, Boualem</creatorcontrib><creatorcontrib>Houamel, Dounia</creatorcontrib><creatorcontrib>Delaby, Constance</creatorcontrib><creatorcontrib>Tchernitchko, Dimitri</creatorcontrib><creatorcontrib>Vaulont, Sophie</creatorcontrib><creatorcontrib>Letteron, Philippe</creatorcontrib><creatorcontrib>Thibaudeau, Olivier</creatorcontrib><creatorcontrib>Puy, Hervé</creatorcontrib><creatorcontrib>Gouya, Laurent</creatorcontrib><creatorcontrib>Beaumont, Carole</creatorcontrib><creatorcontrib>Karim, Zoubida</creatorcontrib><title>Hepcidin regulates intrarenal iron handling at the distal nephron</title><title>Kidney international</title><addtitle>Kidney Int</addtitle><description>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 55Fe 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.</description><subject>Animals</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Cell Line</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Hemochromatosis - chemically induced</subject><subject>Hemochromatosis - genetics</subject><subject>Hemochromatosis - metabolism</subject><subject>Hepcidins - deficiency</subject><subject>Hepcidins - genetics</subject><subject>Hepcidins - metabolism</subject><subject>Homeostasis - physiology</subject><subject>In Vitro Techniques</subject><subject>ion transport</subject><subject>Iron - metabolism</subject><subject>kidney tubule</subject><subject>Kidney Tubules, Distal - metabolism</subject><subject>Kidney Tubules, Distal - pathology</subject><subject>Loop of Henle - metabolism</subject><subject>Membrane Proteins - deficiency</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>mineral metabolism</subject><subject>Opossums</subject><subject>pathology</subject><subject>Phenylhydrazines - adverse effects</subject><subject>Receptors, Transferrin - metabolism</subject><subject>renal epithelial cell</subject><issn>0085-2538</issn><issn>1523-1755</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNptkN9LwzAQx4Mobk6ffJeCL4J05kfTtI9jqBMGvuhzyNLLlq1La9IK_vembPogwsFx3Oc-cF-ErgmeEsyKh52dUkzYlGT0BI0JpywlgvNTNMa44CnlrBihixC2OM4lw-doRFlOOMd0jGYLaLWtrEs8rPtadRAS6zqvPDhVJ9Y3LtkoV9XWrRPVJd0GksqGLu4ctJu4vkRnRtUBro59gt6fHt_mi3T5-vwyny1TnWHcpUIYBbkuqyI3mNNsRZUxpKggL0xGMddKKV5CoUzGMNVaAF-JXAguwLCszNkE3R28rW8-egid3Nugoa6Vg6YPkmQZY0XOKI3o7R902_Q-_jNQTOS0jBWp-wOlfROCByNbb_fKf0mC5ZCs3Fk5JBuPBufN0dmv9lD9sj9RRoAfAIghfFrwMmgLTkNlPehOVo39V_wNxGeEkA</recordid><startdate>20131001</startdate><enddate>20131001</enddate><creator>Moulouel, Boualem</creator><creator>Houamel, Dounia</creator><creator>Delaby, Constance</creator><creator>Tchernitchko, Dimitri</creator><creator>Vaulont, Sophie</creator><creator>Letteron, Philippe</creator><creator>Thibaudeau, Olivier</creator><creator>Puy, Hervé</creator><creator>Gouya, Laurent</creator><creator>Beaumont, Carole</creator><creator>Karim, Zoubida</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20131001</creationdate><title>Hepcidin regulates intrarenal iron handling at the distal nephron</title><author>Moulouel, Boualem ; 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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 55Fe 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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23615502</pmid><doi>10.1038/ki.2013.142</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cation Transport Proteins - metabolism Cell Line Cells, Cultured Disease Models, Animal Hemochromatosis - chemically induced Hemochromatosis - genetics Hemochromatosis - metabolism Hepcidins - deficiency Hepcidins - genetics Hepcidins - metabolism Homeostasis - physiology In Vitro Techniques ion transport Iron - metabolism kidney tubule Kidney Tubules, Distal - metabolism Kidney Tubules, Distal - pathology Loop of Henle - metabolism Membrane Proteins - deficiency Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Knockout mineral metabolism Opossums pathology Phenylhydrazines - adverse effects Receptors, Transferrin - metabolism renal epithelial cell |
title | Hepcidin regulates intrarenal iron handling at the distal nephron |
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