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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

Authors

Bo Zeng

Gui-Lan Chen

Eliana Garcia-Vaz

Sunil Bhandari

Nikoleta Daskoulidou

Lisa M. Berglund

Hongni Jiang

Thomas Hallett

Lu-Ping Zhou

Li Huang

Zi-Hao Xu

Viji Nair

Robert G. Nelson

Wenjun Ju

Matthias Kretzler

Stephen L. Atkin

Maria F. Gomez

Shang-Zhong Xu



Abstract

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 Ca2+-dependent and accompanied by ORAI1 internalization. Amnionless (AMN) associates with ORAIs and forms STIM/ORAI/AMN complexes after Ca2+ 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.

Citation

Zeng, B., Chen, G.-L., Garcia-Vaz, E., Bhandari, S., Daskoulidou, N., Berglund, L. M., Jiang, H., Hallett, T., Zhou, L.-P., Huang, L., Xu, Z.-H., Nair, V., Nelson, R. G., Ju, W., Kretzler, M., Atkin, S. L., Gomez, M. F., & Xu, S.-Z. (2017). ORAI channels are critical for receptor-mediated endocytosis of albumin. Nature communications, 8(1), Article 1920. https://doi.org/10.1038/s41467-017-02094-y

Journal Article Type Article
Acceptance Date Nov 6, 2017
Online Publication Date Dec 4, 2017
Publication Date Dec 4, 2017
Deposit Date Apr 25, 2019
Publicly Available Date Apr 26, 2019
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number 1920
DOI https://doi.org/10.1038/s41467-017-02094-y
Keywords Kidney; Nephrons; Physiology
Public URL https://hull-repository.worktribe.com/output/1647103
Publisher URL https://www.nature.com/articles/s41467-017-02094-y
Contract Date Apr 25, 2019

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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/.






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