ORAI channels are critical for receptor-mediated endocytosis of albumin

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 and Shang-Zhong Xu ()
Additional contact information
Bo Zeng: University of Hull
Gui-Lan Chen: University of Hull
Eliana Garcia-Vaz: Lund University
Sunil Bhandari: Department of Renal Medicine and Hull York Medical School, Hull Royal Infirmary, Hull and East Yorkshire Hospitals NHS Trust
Nikoleta Daskoulidou: University of Hull
Lisa M. Berglund: Lund University
Hongni Jiang: University of Hull
Thomas Hallett: University of Hull
Lu-Ping Zhou: Southwest Medical University
Li Huang: Southwest Medical University
Zi-Hao Xu: Southwest Medical University
Viji Nair: University of Michigan
Robert G. Nelson: Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Wenjun Ju: University of Michigan
Matthias Kretzler: University of Michigan
Stephen L. Atkin: University of Hull
Maria F. Gomez: Lund University
Shang-Zhong Xu: University of Hull

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02094-y

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