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Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells

We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl(2)), the leve...

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Autores principales: Fujiki, K, Inamura, H, Matsuoka, M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454314/
https://www.ncbi.nlm.nih.gov/pubmed/25118938
http://dx.doi.org/10.1038/cddis.2014.339
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author Fujiki, K
Inamura, H
Matsuoka, M
author_facet Fujiki, K
Inamura, H
Matsuoka, M
author_sort Fujiki, K
collection PubMed
description We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl(2)), the level of Notch intracellular domain (NICD), the cleaved form of the Notch1 receptor, was increased and accumulated in the nuclear fraction. Knockdown of Notch1 with siRNA or treatment with the γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), prevented CdCl(2)-induced morphological change of HK-2 cells and reduction of cell viability. Knockdown of Jagged1 or Jagged2, the ligands of the Notch1 receptor, partially suppressed cadmium cytotoxicity. Inhibition of p53 activity with pifithrin-α or inhibition of PI3K with LY294002 suppressed CdCl(2)-induced cellular damage and elevation of Notch1-NICD. In addition, treatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, and the insulin-like growth factor-1 receptor inhibitor, PPP, suppressed both Notch1-NICD accumulation and Akt phosphorylation in HK-2 cells exposed to CdCl(2). However, knockdown of Notch1 did not affect CdCl(2)-induced p53 accumulation and phosphorylation but suppressed phosphorylation of EGFR, Akt, and p70 S6 kinase. Depletion of Notch1 suppressed CdCl(2)-induced reduction of E-cadherin expression and elevation of Snail expression. Furthermore, treatment with SB216763, an inhibitor of glycogen synthase kinase-3, suppressed the potency of LY294002 treatment to reduce Snail expression in HK-2 cells exposed to CdCl(2). Knockdown of Snail with siRNA partially prevented HK-2 cells from CdCl(2)-induced reduction of E-cadherin expression and cellular damage. These results suggest that cadmium exposure induces the activation of Notch1 signaling in renal proximal tubular cells with cooperative activation by the p53 and PI3K/Akt signaling pathways; the resultant expression of Snail, a repressor of E-cadherin expression, might lead to cellular damage by decreasing cell–cell adhesion.
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spelling pubmed-44543142015-06-15 Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells Fujiki, K Inamura, H Matsuoka, M Cell Death Dis Original Article We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl(2)), the level of Notch intracellular domain (NICD), the cleaved form of the Notch1 receptor, was increased and accumulated in the nuclear fraction. Knockdown of Notch1 with siRNA or treatment with the γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), prevented CdCl(2)-induced morphological change of HK-2 cells and reduction of cell viability. Knockdown of Jagged1 or Jagged2, the ligands of the Notch1 receptor, partially suppressed cadmium cytotoxicity. Inhibition of p53 activity with pifithrin-α or inhibition of PI3K with LY294002 suppressed CdCl(2)-induced cellular damage and elevation of Notch1-NICD. In addition, treatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, and the insulin-like growth factor-1 receptor inhibitor, PPP, suppressed both Notch1-NICD accumulation and Akt phosphorylation in HK-2 cells exposed to CdCl(2). However, knockdown of Notch1 did not affect CdCl(2)-induced p53 accumulation and phosphorylation but suppressed phosphorylation of EGFR, Akt, and p70 S6 kinase. Depletion of Notch1 suppressed CdCl(2)-induced reduction of E-cadherin expression and elevation of Snail expression. Furthermore, treatment with SB216763, an inhibitor of glycogen synthase kinase-3, suppressed the potency of LY294002 treatment to reduce Snail expression in HK-2 cells exposed to CdCl(2). Knockdown of Snail with siRNA partially prevented HK-2 cells from CdCl(2)-induced reduction of E-cadherin expression and cellular damage. These results suggest that cadmium exposure induces the activation of Notch1 signaling in renal proximal tubular cells with cooperative activation by the p53 and PI3K/Akt signaling pathways; the resultant expression of Snail, a repressor of E-cadherin expression, might lead to cellular damage by decreasing cell–cell adhesion. Nature Publishing Group 2014-08 2014-08-14 /pmc/articles/PMC4454314/ /pubmed/25118938 http://dx.doi.org/10.1038/cddis.2014.339 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Fujiki, K
Inamura, H
Matsuoka, M
Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
title Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
title_full Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
title_fullStr Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
title_full_unstemmed Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
title_short Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
title_sort detrimental effects of notch1 signaling activated by cadmium in renal proximal tubular epithelial cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454314/
https://www.ncbi.nlm.nih.gov/pubmed/25118938
http://dx.doi.org/10.1038/cddis.2014.339
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