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Orai channels are critical for receptor-mediated endocytosis of albumin

Zeng, Bo; Chen, Gui Lan; Garcia-Vaz, Eliana LU ; Bhandari, Sunil; Daskoulidou, Nikoleta; Berglund, Lisa M. LU ; Jiang, Hongni; Hallett, Thomas; Zhou, Lu Ping and Huang, Li, et al. (2017) In Nature Communications 8(1).
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... (More)

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.

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Nature Communications
volume
8
issue
1
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Nature Publishing Group
external identifiers
  • scopus:85037152842
  • wos:000417029900010
ISSN
2041-1723
DOI
10.1038/s41467-017-02094-y
language
English
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yes
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8d9d378b-f198-42e4-a5f5-dd458c673155
date added to LUP
2017-12-21 12:37:18
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2018-05-20 04:39:37
@article{8d9d378b-f198-42e4-a5f5-dd458c673155,
  abstract     = {<p>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 Ca<sup>2+</sup>-dependent and accompanied by ORAI1 internalization. Amnionless (AMN) associates with ORAIs and forms STIM/ORAI/AMN complexes after Ca<sup>2+</sup> 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.</p>},
  articleno    = {1920},
  author       = {Zeng, Bo and Chen, Gui Lan and Garcia-Vaz, Eliana and Bhandari, Sunil and Daskoulidou, Nikoleta and Berglund, Lisa M. and Jiang, Hongni and Hallett, Thomas and Zhou, Lu Ping and Huang, Li and Xu, Zi Hao and Nair, Viji and Nelson, Robert G. and Ju, Wenjun and Kretzler, Matthias and Atkin, Stephen L. and Gomez, Maria F. and Xu, Shang Zhong},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Orai channels are critical for receptor-mediated endocytosis of albumin},
  url          = {http://dx.doi.org/10.1038/s41467-017-02094-y},
  volume       = {8},
  year         = {2017},
}