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  • Title: Insulin Increases Expression of TRPC6 Channels in Podocytes by a Calcineurin-Dependent Pathway.
    Author: Xia S, Liu Y, Li X, Thilo F, Tepel M.
    Journal: Cell Physiol Biochem; 2016; 38(2):659-69. PubMed ID: 26849622.
    Abstract:
    BACKGROUND/AIMS: Insulin signaling to podocytes is relevant for the function of the glomerulus. Now, we tested the hypothesis that insulin increases the surface expression of canonical transient receptor potential canonical type 6 (TRPC6) channels in podocytes by a calcineurin-dependent pathway. METHODS: We used quantitative RT-PCR, immunoblotting, immunofluorescence and fluorescence spectrophotometry in cultured podocytes. Activation of Nuclear Factor of Activated T-cells (NFATc1) was measured using a specific calorimetric assay. RESULTS: Insulin increased the expression of TRPC6 transcripts and protein in podocytes. Insulin increased TRPC6 transcripts in a time and dose-dependent manner. The insulin-induced elevation of TRPC6 transcripts was blocked in the presence of tacrolimus, cyclosporine A, and NFAT-inhibitor (each p < 0.01 by ANOVA and Bonferroni's multiple comparison test). Transcripts of NOX4, another target gene of the calcineurin-NFAT pathway, were affected in a similar way. Immunoblotting showed that the administration of 100 nmol/L insulin increased TRPC6-proteins 2-fold within 48 hours. Insulin increased the activity of NFATc1 in nuclear extracts (p < 0.001) whereas tacrolimus, cyclosporine A, and NFAT-inhibitor blocked that insulin effect (p < 0.001; two way ANOVA). Immunofluorescence showed that insulin increased TRPC6-expression on the cell surface. Fluorescence-spectrophotometry and manganese quench experiments indicated that the increased TRPC6-expression after insulin administration was accompanied by an elevated transplasmamembrane cation influx. Insulin-stimulated surface expression of TRPC6 as well as transplasmamembrane cation influx could be reduced by pretreatment with tacrolimus. CONCLUSION: Insulin increases the expression of TRPC6 channels in podocytes by activation of the calcineurin-dependent pathway.
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