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ORAI channels are critical for receptor-mediated endocytosis of albumin and govern the pathogenesis of diabetic nephropathy

Bo Zeng;Gui-Lan Chen;Eliana Garcia-Vaz;Sunil Bhandari;Nikoleta Daskoulidou;Lisa M. Berglund;Hongni Jiang;Li Huang;Qin Wan;Stephen L.Atkin;Maria F.Gomez;Shang-Zhong Xu

  Impaired albumin reabsorption by proximal tubular epithelial cells(PTECs) has been highlighted in diabetic nephropathy(DN), but little is known about the molecular mechanisms. Here we find that the Ca~(2+) release-activated Ca~(2+)(CRAC) channels, ORAI1-3, are preferentially expressed in PTECs and down-regulated in patients with DN. Hyperglycaemia or blockade of insulin signalling reduces the expression of ORAI1-3. Inhibition of ORAI channels by BTP2 and diethylstilbestrol or silencing of ORAI expression impairs albumin uptake. In vivo injection of BTP2 exacerbates albuminuria in streptozotocin-induced and Akita diabetic mice. The endocytosis of albumin is Ca~(2+)-dependent and accompanied by ORAI1 internalization in PTECs. Amnionless(AMN) associates with ORAIs and forms STIM/ORAI/AMN complexes after internal Ca~(2+) store depletion. STIM1/ORAI1 colocalizes with clathrin, but not with caveolin, at the apical membrane of PTECs, which determines clathrin-mediated endocytosis of albumin. These findings provide insights into the molecular mechanisms of protein reabsorption and novel potential targets for treating diabetic proteinuria.……