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ORAI channels are critical for receptor-mediated endocytosis of albumin

Impaired albumin reabsorption by proximal tubular epithelial cells (PTECs) has been highlighted in diabetic nephropathy (DN), but little is known about the underlying molecular mechanisms. Here we find that ORAI1-3, are preferentially expressed in PTECs and downregulated in patients with DN. Hypergl...

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Autores principales: Zeng, Bo, Chen, Gui-Lan, Garcia-Vaz, Eliana, Bhandari, Sunil, Daskoulidou, Nikoleta, Berglund, Lisa M., Jiang, Hongni, Hallett, Thomas, Zhou, Lu-Ping, Huang, Li, Xu, Zi-Hao, Nair, Viji, Nelson, Robert G., Ju, Wenjun, Kretzler, Matthias, Atkin, Stephen L., Gomez, Maria F., Xu, Shang-Zhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714946/
https://www.ncbi.nlm.nih.gov/pubmed/29203863
http://dx.doi.org/10.1038/s41467-017-02094-y
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author Zeng, Bo
Chen, Gui-Lan
Garcia-Vaz, Eliana
Bhandari, Sunil
Daskoulidou, Nikoleta
Berglund, Lisa M.
Jiang, Hongni
Hallett, Thomas
Zhou, Lu-Ping
Huang, Li
Xu, Zi-Hao
Nair, Viji
Nelson, Robert G.
Ju, Wenjun
Kretzler, Matthias
Atkin, Stephen L.
Gomez, Maria F.
Xu, Shang-Zhong
author_facet Zeng, Bo
Chen, Gui-Lan
Garcia-Vaz, Eliana
Bhandari, Sunil
Daskoulidou, Nikoleta
Berglund, Lisa M.
Jiang, Hongni
Hallett, Thomas
Zhou, Lu-Ping
Huang, Li
Xu, Zi-Hao
Nair, Viji
Nelson, Robert G.
Ju, Wenjun
Kretzler, Matthias
Atkin, Stephen L.
Gomez, Maria F.
Xu, Shang-Zhong
author_sort Zeng, Bo
collection PubMed
description Impaired albumin reabsorption by proximal tubular epithelial cells (PTECs) has been highlighted in diabetic nephropathy (DN), but little is known about the underlying molecular mechanisms. Here we find that ORAI1-3, are preferentially expressed in PTECs and downregulated in patients with DN. Hyperglycemia or blockade of insulin signaling reduces the expression of ORAI1-3. Inhibition of ORAI channels by BTP2 and diethylstilbestrol or silencing of ORAI expression impairs albumin uptake. Transgenic mice expressing a dominant-negative Orai1 mutant (E108Q) increases albuminuria, and in vivo injection of BTP2 exacerbates albuminuria in streptozotocin-induced and Akita diabetic mice. The albumin endocytosis is Ca(2+)-dependent and accompanied by ORAI1 internalization. Amnionless (AMN) associates with ORAIs and forms STIM/ORAI/AMN complexes after Ca(2+) store depletion. STIM1/ORAI1 colocalizes with clathrin, but not with caveolin, at the apical membrane of PTECs, which determines clathrin-mediated endocytosis. These findings provide insights into the mechanisms of protein reabsorption and potential targets for treating diabetic proteinuria.
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spelling pubmed-57149462017-12-06 ORAI channels are critical for receptor-mediated endocytosis of albumin Zeng, Bo Chen, Gui-Lan Garcia-Vaz, Eliana Bhandari, Sunil Daskoulidou, Nikoleta Berglund, Lisa M. Jiang, Hongni Hallett, Thomas Zhou, Lu-Ping Huang, Li Xu, Zi-Hao Nair, Viji Nelson, Robert G. Ju, Wenjun Kretzler, Matthias Atkin, Stephen L. Gomez, Maria F. Xu, Shang-Zhong Nat Commun Article Impaired albumin reabsorption by proximal tubular epithelial cells (PTECs) has been highlighted in diabetic nephropathy (DN), but little is known about the underlying molecular mechanisms. Here we find that ORAI1-3, are preferentially expressed in PTECs and downregulated in patients with DN. Hyperglycemia or blockade of insulin signaling reduces the expression of ORAI1-3. Inhibition of ORAI channels by BTP2 and diethylstilbestrol or silencing of ORAI expression impairs albumin uptake. Transgenic mice expressing a dominant-negative Orai1 mutant (E108Q) increases albuminuria, and in vivo injection of BTP2 exacerbates albuminuria in streptozotocin-induced and Akita diabetic mice. The albumin endocytosis is Ca(2+)-dependent and accompanied by ORAI1 internalization. Amnionless (AMN) associates with ORAIs and forms STIM/ORAI/AMN complexes after Ca(2+) store depletion. STIM1/ORAI1 colocalizes with clathrin, but not with caveolin, at the apical membrane of PTECs, which determines clathrin-mediated endocytosis. These findings provide insights into the mechanisms of protein reabsorption and potential targets for treating diabetic proteinuria. Nature Publishing Group UK 2017-12-04 /pmc/articles/PMC5714946/ /pubmed/29203863 http://dx.doi.org/10.1038/s41467-017-02094-y Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zeng, Bo
Chen, Gui-Lan
Garcia-Vaz, Eliana
Bhandari, Sunil
Daskoulidou, Nikoleta
Berglund, Lisa M.
Jiang, Hongni
Hallett, Thomas
Zhou, Lu-Ping
Huang, Li
Xu, Zi-Hao
Nair, Viji
Nelson, Robert G.
Ju, Wenjun
Kretzler, Matthias
Atkin, Stephen L.
Gomez, Maria F.
Xu, Shang-Zhong
ORAI channels are critical for receptor-mediated endocytosis of albumin
title ORAI channels are critical for receptor-mediated endocytosis of albumin
title_full ORAI channels are critical for receptor-mediated endocytosis of albumin
title_fullStr ORAI channels are critical for receptor-mediated endocytosis of albumin
title_full_unstemmed ORAI channels are critical for receptor-mediated endocytosis of albumin
title_short ORAI channels are critical for receptor-mediated endocytosis of albumin
title_sort orai channels are critical for receptor-mediated endocytosis of albumin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714946/
https://www.ncbi.nlm.nih.gov/pubmed/29203863
http://dx.doi.org/10.1038/s41467-017-02094-y
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