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J Cell Physiol ; 230(11): 2776-87, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25825272

RESUMEN

Hyperosmolarity decreases claudin-2 expression in renal tubular epithelial cells, but the molecular mechanism remains undefined. Here, we found that the hyperosmolarity-induced decrease in claudin-2 expression is inhibited by Go6983, a non-selective protein kinase C (PKC) inhibitor, and PKCß specific inhibitor in Madin-Darby canine kidney II cells. Hyperosmolarity increased intracellular free Ca(2+) concentration and phosphorylated PKCß level, which were inhibited by RN-1734, an antagonist of transient receptor potential vanilloid 4 channel. Phorbol 12-myristate 13-acetate, a PKC activator, decreased claudin-2 expression. These results indicate hyperosmolarity decreases claudin-2 expression mediated by the activation of RN-1734-sensitive channel and PKCß. Hyperosmolarity decreased promoter activity of claudin-2, which was inhibited by Go6983 and PKCß inhibitor similar to those in real-time PCR and Western blotting. The effect of hyperosmolarity on promoter activity was not observed in the construct of -469/-6, a deletion mutant. Claudin-2 has hyperosmolarity-sensitive region in its promoter, which includes GATA binding site. Hyperosmolarity decreased the nuclear level of GATA-2, which was inhibited by Go6983 and PKCß inhibitor. Mutation of GATA binding site decreased the basal promoter activity and inhibited the effect of hyperosmolarity. In contrast, the hyperosmolarity-induced decrease in reporter activity and claudin-2 expression were rescued by over-expression of wild type GATA-2. Chromatin immunoprecipitation assay showed that GATA-2 bound to promoter region of claudin-2. These results suggest that hyperosmolarity decreases the expression level of claudin-2 via a decrease in PKCß-dependent GATA-2 transcriptional activity in renal tubular epithelial cells.


Asunto(s)
Claudina-2/biosíntesis , Factor de Transcripción GATA2/biosíntesis , Concentración Osmolar , Proteína Quinasa C beta/biosíntesis , Animales , Sitios de Unión , Señalización del Calcio/efectos de los fármacos , Claudina-2/genética , Perros , Factor de Transcripción GATA2/genética , Regulación de la Expresión Génica/efectos de los fármacos , Indoles/administración & dosificación , Túbulos Renales Proximales/metabolismo , Células de Riñón Canino Madin Darby , Maleimidas/administración & dosificación , Regiones Promotoras Genéticas , Proteína Quinasa C beta/antagonistas & inhibidores , Ratas , Sulfonamidas , Acetato de Tetradecanoilforbol/administración & dosificación
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