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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Kidney international 2013-10, Vol.84 (4), p.756-766
Hauptverfasser: Moulouel, Boualem, Houamel, Dounia, Delaby, Constance, Tchernitchko, Dimitri, Vaulont, Sophie, Letteron, Philippe, Thibaudeau, Olivier, Puy, Hervé, Gouya, Laurent, Beaumont, Carole, Karim, Zoubida
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 766
container_issue 4
container_start_page 756
container_title Kidney international
container_volume 84
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
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1443386322</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0085253815560225</els_id><sourcerecordid>1443386322</sourcerecordid><originalsourceid>FETCH-LOGICAL-c400t-77fae6c9d86f0524b2aff18de68f4205caaa59e8af4302cc7e5b767757ef34963</originalsourceid><addsrcrecordid>eNptkN9LwzAQx4Mobk6ffJeCL4J05kfTtI9jqBMGvuhzyNLLlq1La9IK_vembPogwsFx3Oc-cF-ErgmeEsyKh52dUkzYlGT0BI0JpywlgvNTNMa44CnlrBihixC2OM4lw-doRFlOOMd0jGYLaLWtrEs8rPtadRAS6zqvPDhVJ9Y3LtkoV9XWrRPVJd0GksqGLu4ctJu4vkRnRtUBro59gt6fHt_mi3T5-vwyny1TnWHcpUIYBbkuqyI3mNNsRZUxpKggL0xGMddKKV5CoUzGMNVaAF-JXAguwLCszNkE3R28rW8-egid3Nugoa6Vg6YPkmQZY0XOKI3o7R902_Q-_jNQTOS0jBWp-wOlfROCByNbb_fKf0mC5ZCs3Fk5JBuPBufN0dmv9lD9sj9RRoAfAIghfFrwMmgLTkNlPehOVo39V_wNxGeEkA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1437629629</pqid></control><display><type>article</type><title>Hepcidin regulates intrarenal iron handling at the distal nephron</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>ProQuest Central UK/Ireland</source><source>Alma/SFX Local Collection</source><creator>Moulouel, Boualem ; Houamel, Dounia ; Delaby, Constance ; Tchernitchko, Dimitri ; Vaulont, Sophie ; Letteron, Philippe ; Thibaudeau, Olivier ; Puy, Hervé ; Gouya, Laurent ; Beaumont, Carole ; Karim, Zoubida</creator><creatorcontrib>Moulouel, Boualem ; Houamel, Dounia ; Delaby, Constance ; Tchernitchko, Dimitri ; Vaulont, Sophie ; Letteron, Philippe ; Thibaudeau, Olivier ; Puy, Hervé ; Gouya, Laurent ; Beaumont, Carole ; Karim, Zoubida</creatorcontrib><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><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 ; Houamel, Dounia ; Delaby, Constance ; Tchernitchko, Dimitri ; Vaulont, Sophie ; Letteron, Philippe ; Thibaudeau, Olivier ; Puy, Hervé ; Gouya, Laurent ; Beaumont, Carole ; Karim, Zoubida</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-77fae6c9d86f0524b2aff18de68f4205caaa59e8af4302cc7e5b767757ef34963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Cation Transport Proteins - metabolism</topic><topic>Cell Line</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Hemochromatosis - chemically induced</topic><topic>Hemochromatosis - genetics</topic><topic>Hemochromatosis - metabolism</topic><topic>Hepcidins - deficiency</topic><topic>Hepcidins - genetics</topic><topic>Hepcidins - metabolism</topic><topic>Homeostasis - physiology</topic><topic>In Vitro Techniques</topic><topic>ion transport</topic><topic>Iron - metabolism</topic><topic>kidney tubule</topic><topic>Kidney Tubules, Distal - metabolism</topic><topic>Kidney Tubules, Distal - pathology</topic><topic>Loop of Henle - metabolism</topic><topic>Membrane Proteins - deficiency</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>mineral metabolism</topic><topic>Opossums</topic><topic>pathology</topic><topic>Phenylhydrazines - adverse effects</topic><topic>Receptors, Transferrin - metabolism</topic><topic>renal epithelial cell</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Kidney international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moulouel, Boualem</au><au>Houamel, Dounia</au><au>Delaby, Constance</au><au>Tchernitchko, Dimitri</au><au>Vaulont, Sophie</au><au>Letteron, Philippe</au><au>Thibaudeau, Olivier</au><au>Puy, Hervé</au><au>Gouya, Laurent</au><au>Beaumont, Carole</au><au>Karim, Zoubida</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepcidin regulates intrarenal iron handling at the distal nephron</atitle><jtitle>Kidney international</jtitle><addtitle>Kidney Int</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>84</volume><issue>4</issue><spage>756</spage><epage>766</epage><pages>756-766</pages><issn>0085-2538</issn><eissn>1523-1755</eissn><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 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>
fulltext fulltext
identifier ISSN: 0085-2538
ispartof Kidney international, 2013-10, Vol.84 (4), p.756-766
issn 0085-2538
1523-1755
language eng
recordid cdi_proquest_miscellaneous_1443386322
source MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T02%3A17%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hepcidin%20regulates%20intrarenal%20iron%20handling%20at%20the%20distal%20nephron&rft.jtitle=Kidney%20international&rft.au=Moulouel,%20Boualem&rft.date=2013-10-01&rft.volume=84&rft.issue=4&rft.spage=756&rft.epage=766&rft.pages=756-766&rft.issn=0085-2538&rft.eissn=1523-1755&rft_id=info:doi/10.1038/ki.2013.142&rft_dat=%3Cproquest_cross%3E1443386322%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1437629629&rft_id=info:pmid/23615502&rft_els_id=S0085253815560225&rfr_iscdi=true