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, Shang Zhong Xu

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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.

Originalspråkengelska
Artikelnummer1920
TidskriftNature Communications
Volym8
Nummer1
DOI
StatusPublished - 2017 dec. 1

Ämnesklassifikation (UKÄ)

  • Endokrinologi och diabetes

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