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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.

Journal Article Type Article
Publication Date Dec 4, 2017
Journal Nature Communications
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number 1920
APA6 Citation Zeng, B., Chen, G., Garcia-Vaz, E., Bhandari, S., Daskoulidou, N., Berglund, L. M., …Xu, S. (2017). ORAI channels are critical for receptor-mediated endocytosis of albumin. Nature communications, 8(1), https://doi.org/10.1038/s41467-017-02094-y
DOI https://doi.org/10.1038/s41467-017-02094-y
Keywords Kidney; Nephrons; Physiology
Publisher URL https://www.nature.com/articles/s41467-017-02094-y

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