Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02094-y
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Funding
- British Heart Foundation
- National Natural Science Foundation of China [31300965, 31300949]
- China Scholarship Council
- University PhD studentship
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [P30 DK081943]
- National Institute of Diabetes and Digestive and Kidney Diseases
- Swedish Research Council [2011-3900, 2013-0700]
- Albert Pahlsson foundation
- Swedish Foundation for Strategic Research
- Innovative Medicines Initiative [115006, 115974]
- European Union
- Horizon research and innovation programme
- EFPIA
- Leverhulme Trust
- Hull York Medical School Pump Priming Award
- Diabetes foundation
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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 down-regulated 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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