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ORAI channels are critical for receptor-mediated endocytosis of albumin

Author

Listed:
  • Bo Zeng

    (University of Hull
    Southwest Medical University)

  • Gui-Lan Chen

    (University of Hull
    Southwest Medical University)

  • 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
    Weill Cornell Medical College Qatar, PO Box)

  • Maria F. Gomez

    (Lund University)

  • Shang-Zhong Xu

    (University of Hull)

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.

Suggested Citation

  • 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. Nels, 2017. "ORAI channels are critical for receptor-mediated endocytosis of albumin," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02094-y
    DOI: 10.1038/s41467-017-02094-y
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