ORAI channels are critical for receptor-mediated endocytosis of albumin.
Nat Commun
; 8(1): 1920, 2017 12 04.
Article
em En
| MEDLINE
| ID: mdl-29203863
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Cálcio
/
Diabetes Mellitus Experimental
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Diabetes Mellitus Tipo 1
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Nefropatias Diabéticas
/
Albuminas
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Albuminúria
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Células Epiteliais
/
Proteína ORAI1
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Proteína ORAI2
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Túbulos Renais Proximais
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article