Dataset Information

Bestrophin 1 promotes epithelial-to-mesenchymal transition of renal collecting duct cells.

ABSTRACT: Bestrophin 1 (Best1) controls intracellular Ca(2+) concentration, induces Ca(2+)-activated Cl(-) conductance, and increases proliferation of colon carcinoma cells. Here, we show that expression of Best1 in mouse renal collecting duct (CD) cells causes i) an increase in cell proliferation, ii) a loss of amiloride-sensitive Na(+) absorption, iii) induction of Ca(2+)-dependent Cl(-) conductance (CaCC), and iv) epithelial-to-mesenchymal transition. During conditions of high proliferation or when we exposed CD cells to serum or TGF-beta1, we observed upregulation of Best1, increased CaCC, redistribution of the epithelial-to-mesenchymal transition marker beta-catenin, and upregulation of vimentin. In contrast, suppression of Best1 by RNAi inhibited proliferation, reduced CaCC, and downregulated markers of EMT. CaCC and expression of Best1 were independent of the cell cycle but clearly correlated to cell proliferation and cell density. During renal inflammation in LPS-treated mice or after unilateral ureteral obstruction, we observed transient upregulation of Best1. These data indicate that repression of cell proliferation, CaCC, and expression of Best1 occurs during mesenchymal-to-epithelial transition once CD cells polarize and terminally differentiate. These results may suggest a role for Best1 in renal fibrosis and tissue repair.

SUBMITTER: Aldehni F

PROVIDER: S-EPMC2709680 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Bestrophin 1 promotes epithelial-to-mesenchymal transition of renal collecting duct cells.

Aldehni Fadi F Spitzner Melanie M Martins Joana Raquel JR Barro-Soria René R Schreiber Rainer R Kunzelmann Karl K

Journal of the American Society of Nephrology : JASN 20090521 7

Bestrophin 1 (Best1) controls intracellular Ca(2+) concentration, induces Ca(2+)-activated Cl(-) conductance, and increases proliferation of colon carcinoma cells. Here, we show that expression of Best1 in mouse renal collecting duct (CD) cells causes i) an increase in cell proliferation, ii) a loss of amiloride-sensitive Na(+) absorption, iii) induction of Ca(2+)-dependent Cl(-) conductance (CaCC), and iv) epithelial-to-mesenchymal transition. During conditions of high proliferation or when we ...[more]

PMID: 19470678

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Project description:Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.

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Bestrophin 1 promotes epithelial-to-mesenchymal transition of renal collecting duct cells.

Publications

Bestrophin 1 promotes epithelial-to-mesenchymal transition of renal collecting duct cells.

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