@article { , title = {ORAI channels are critical for receptor-mediated endocytosis of albumin}, 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.}, doi = {10.1038/s41467-017-02094-y}, issue = {1}, journal = {Nature Communications}, publicationstatus = {Published}, publisher = {Nature Publishing Group}, url = {https://hull-repository.worktribe.com/output/1647103}, volume = {8}, keyword = {Health and Health Inequalities, Kidney, Nephrons, Physiology}, year = {2017}, 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} }