1. ORAI channels are critical for receptor-mediated endocytosis of albumin
- Author
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Thomas Hallett, Stephen L. Atkin, Lisa Berglund, Eliana Garcia-Vaz, Wenjun Ju, Zi Hao Xu, Hongni Jiang, Gui-Lan Chen, Sunil Bhandari, Li Huang, Matthias Kretzler, Bo Zeng, Robert G. Nelson, Viji Nair, Shang-Zhong Xu, Lu Ping Zhou, Maria F. Gomez, and Nikoleta Daskoulidou
- Subjects
Male ,0301 basic medicine ,ORAI1 Protein ,General Physics and Astronomy ,Kidney ,Kidney Tubules, Proximal ,Mice ,0302 clinical medicine ,Caveolin ,Anilides ,Diabetic Nephropathies ,lcsh:Science ,Multidisciplinary ,biology ,Reabsorption ,ORAI1 ,Chemistry ,Amnionless ,Middle Aged ,Calcium Channel Blockers ,Endocytosis ,3. Good health ,Cell biology ,030220 oncology & carcinogenesis ,Female ,Science ,ORAI2 Protein ,Down-Regulation ,Mice, Transgenic ,Caveolins ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Albumins ,Thiadiazoles ,Albuminuria ,Animals ,Humans ,Estrogens, Non-Steroidal ,Stromal Interaction Molecule 1 ,Diethylstilbestrol ,Membrane Proteins ,Epithelial Cells ,General Chemistry ,Receptor-mediated endocytosis ,Apical membrane ,Renal Reabsorption ,Clathrin ,Insulin receptor ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Case-Control Studies ,Hyperglycemia ,Mutation ,biology.protein ,Calcium ,lcsh:Q ,Calcium Channels - 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., 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.
- Published
- 2017