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rdf:type |
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lifeskim:mentions |
umls-concept:C0014257,
umls-concept:C0024501,
umls-concept:C0035647,
umls-concept:C0078058,
umls-concept:C0205374,
umls-concept:C0332281,
umls-concept:C0439799,
umls-concept:C0596235,
umls-concept:C0597357,
umls-concept:C0721534,
umls-concept:C1256770,
umls-concept:C1947912
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pubmed:issue |
45
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pubmed:dateCreated |
2010-11-10
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pubmed:abstractText |
Klotho is a circulating protein, and Klotho deficiency disturbs endothelial integrity, but the molecular mechanism is not fully clarified. We report that vascular endothelium in Klotho-deficient mice showed hyperpermeability with increased apoptosis and down-regulation of vascular endothelial (VE)-cadherin because of an increase in VEGF-mediated internal calcium concentration ([Ca(2+)]i) influx and hyperactivation of Ca(2+)-dependent proteases. Immunohistochemical analysis, the pull-down assay using Klotho-fixed agarose, and FRET confocal imaging confirmed that Klotho protein binds directly to VEGF receptor 2 (VEGFR-2) and endothelial, transient-receptor potential canonical Ca(2+) channel 1 (TRPC-1) and strengthens the association to promote their cointernalization. An in vitro mutagenesis study revealed that the second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of VEGFR-2 and the third extracellular loop of TRPC-1. In Klotho-deficient endothelial cells, VEGF-mediated internalization of the VEGFR-2/TRPC-1 complex was impaired, and surface TRPC-1 expression increased 2.2-fold; these effects were reversed by supplementation of Klotho protein. VEGF-mediated elevation of [Ca(2+)]i was sustained at higher levels in an extracellular Ca(2+)-dependent manner, and normalization of TRCP-1 expression restored the abnormal [Ca(2+)]i handling. These findings provide evidence that Klotho protein is associated with VEGFR-2/TRPC-1 in causing cointernalization, thus regulating TRPC-1-mediated Ca(2+) entry to maintain endothelial integrity.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-11027545,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-11162628,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-11581493,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-11827703,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-11967236,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-12119304,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-12747958,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-14505576,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-14610049,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-14701853,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-15302783,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-15485693,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-15920022,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-15988589,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-16123266,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-16239475,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-16254217,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-16857972,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-17086194,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-17287345,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-17569864,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20966350-9363890
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1091-6490
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pubmed:author |
pubmed-author:AdachiYasushiY,
pubmed-author:HattaTsuguruT,
pubmed-author:IshikawaKazuhikoK,
pubmed-author:KimuraTaikouT,
pubmed-author:KusabaTetsuroT,
pubmed-author:MatsubaraHiroakiH,
pubmed-author:MatuiAkihiroA,
pubmed-author:MoriYasukiyoY,
pubmed-author:MurakamiManabuM,
pubmed-author:OkigakiMitsuhikoM,
pubmed-author:SasakiSusumuS,
pubmed-author:ShibuyaMasabumiM,
pubmed-author:ShirayamaTakeshiT,
pubmed-author:SonomuraKazuhiroK,
pubmed-author:TandaShujiS
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pubmed:issnType |
Electronic
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pubmed:day |
9
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pubmed:volume |
107
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
19308-13
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pubmed:dateRevised |
2011-7-28
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pubmed:meshHeading |
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pubmed:year |
2010
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pubmed:articleTitle |
Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity.
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pubmed:affiliation |
Department of Cardiovascular and Renal Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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