Bo Zeng
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
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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