ORAI channels are critical for receptor-mediated endocytosis of albumin

• Published in: Nature communications Vol. 8; no. 1; pp. 1920 - 12
• Main Authors: Zeng, Bo, Chen, Gui-Lan, Garcia-Vaz, Eliana, Bhandari, Sunil, Daskoulidou, Nikoleta, Berglund, Lisa M., Jiang, Hongni, Hallett, Thomas, Zhou, Lu-Ping, Huang, Li, Xu, Zi-Hao, Nair, Viji, Nelson, Robert G., Ju, Wenjun, Kretzler, Matthias, Atkin, Stephen L., Gomez, Maria F., Xu, Shang-Zhong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/443; 631/443/272/1684; 692/4022/272; Albumin; Calcium; Calcium channels; Caveolin; Channels; Clathrin; Clinical Medicine; Diabetes; Diabetes mellitus; Diethylstilbestrol; Endocrinology and Diabetes; Endocytosis; Endokrinologi och diabetes; Epithelial cells; Humanities and Social Sciences; Hyperglycemia; Insulin; Internalization; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Molecular modelling; multidisciplinary; Nephropathy; Orai1 protein; Proteinuria; Reabsorption; Rodents; Science; Science (multidisciplinary); Signaling; STIM1 protein; Streptozocin; Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02094-y

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 2+ -dependent and accompanied by ORAI1 internalization. Amnionless (AMN) associates with ORAIs and forms STIM/ORAI/AMN complexes after Ca 2+ 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. Patients with diabetic nephropathy suffer from impaired albumin reabsorption by proximal tubular epithelial cells. Here authors use diabetic and transgenic mouse models and in vitro models to show the cause for this lies in the down regulation and internalization of the ion channels, ORAI1-3.