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1,25(OH)2 D3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells.
Nutrition 2019; 69:110554N

Abstract

OBJECTIVES

Indoxyl sulfate (IS), a uremic toxin, has been shown to promote the epithelial-to-mesenchymal transition (EMT) of human proximal tubular cells and to accelerate the progression of chronic kidney disease (CKD). Despite the well-known protective role of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] in EMT, the effect of 1,25(OH)2 D3 on IS-induced EMT in human proximal tubular epithelial cells and the underlying mechanism remain unclear. The aim of this study was to determine whether IS (0-1 mM) dose-dependently inhibited the protein expression of E-cadherin and increased the protein expression of alpha-smooth muscle actin, N-cadherin, and fibronectin.

METHODS

This study investigated the molecular mechanism by which 1,25(OH)2 D3 attenuates IS-induced EMT. HK-2 human renal tubular epithelial cells was used as the study model, and the MTT assay, Western Blotting, siRNA knockdown technique were used to explore the effects of 1,25(OH)2 D3 on EMT in the presence of IS.

RESULTS

Pretreatment with 1,25(OH)2 D3 inhibited the IS-induced EMT-associated protein expression in HK-2 cells. IS induced the phosphorylation of Akt (S473) and β-catenin (S552) and subsequently increased the nuclear accumulation of β-catenin. Pretreatment with 1,25(OH)2 D3 and LY294002 (phosphoinositide 3-kinase [PIK3] inhibitor) significantly inhibited the IS-induced phosphorylation of Akt and β-catenin, nuclear β-catenin accumulation, and EMT-associated protein expression.

CONCLUSIONS

Results from the present study revealed that the anti-EMT effect of 1,25(OH)2 D3 is likely through inhibition of the PI3K/Akt/β-catenin pathway, which leads to down-regulation of IS-driven EMT-associated protein expression in HK-2 human renal tubular epithelial cells.

Authors+Show Affiliations

Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; Department of Medicine, National Defense Medical Center, Taipei, Taiwan; Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan.Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan.Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan.Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; Department of Medicine, National Defense Medical Center, Taipei, Taiwan.Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.Department of Nutrition, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: Licc@csmu.edu.tw.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31536856

Citation

Chang, Li-Chien, et al. "1,25(OH)2 D3 Attenuates Indoxyl Sulfate-induced Epithelial-to-mesenchymal Cell Transition Via Inactivation of PI3K/Akt/β-catenin Signaling in Renal Tubular Epithelial Cells." Nutrition (Burbank, Los Angeles County, Calif.), vol. 69, 2019, p. 110554.
Chang LC, Sun HL, Tsai CH, et al. 1,25(OH)2 D3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells. Nutrition. 2019;69:110554.
Chang, L. C., Sun, H. L., Tsai, C. H., Kuo, C. W., Liu, K. L., Lii, C. K., ... Li, C. C. (2019). 1,25(OH)2 D3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells. Nutrition (Burbank, Los Angeles County, Calif.), 69, p. 110554. doi:10.1016/j.nut.2019.110554.
Chang LC, et al. 1,25(OH)2 D3 Attenuates Indoxyl Sulfate-induced Epithelial-to-mesenchymal Cell Transition Via Inactivation of PI3K/Akt/β-catenin Signaling in Renal Tubular Epithelial Cells. Nutrition. 2019 Jul 25;69:110554. PubMed PMID: 31536856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 1,25(OH)2 D3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells. AU - Chang,Li-Chien, AU - Sun,Hai-Lun, AU - Tsai,Chia-Han, AU - Kuo,Chia-Wen, AU - Liu,Kai-Li, AU - Lii,Chong-Kuei, AU - Huang,Chin-Shiu, AU - Li,Chien-Chun, Y1 - 2019/07/25/ PY - 2019/03/06/received PY - 2019/05/30/revised PY - 2019/07/11/accepted PY - 2019/9/20/pubmed PY - 2019/9/20/medline PY - 2019/9/20/entrez KW - 1,25(OH)(2) D(3) KW - EMT KW - HK-2 cells KW - Indoxyl sulfate KW - β-catenin SP - 110554 EP - 110554 JF - Nutrition (Burbank, Los Angeles County, Calif.) JO - Nutrition VL - 69 N2 - OBJECTIVES: Indoxyl sulfate (IS), a uremic toxin, has been shown to promote the epithelial-to-mesenchymal transition (EMT) of human proximal tubular cells and to accelerate the progression of chronic kidney disease (CKD). Despite the well-known protective role of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] in EMT, the effect of 1,25(OH)2 D3 on IS-induced EMT in human proximal tubular epithelial cells and the underlying mechanism remain unclear. The aim of this study was to determine whether IS (0-1 mM) dose-dependently inhibited the protein expression of E-cadherin and increased the protein expression of alpha-smooth muscle actin, N-cadherin, and fibronectin. METHODS: This study investigated the molecular mechanism by which 1,25(OH)2 D3 attenuates IS-induced EMT. HK-2 human renal tubular epithelial cells was used as the study model, and the MTT assay, Western Blotting, siRNA knockdown technique were used to explore the effects of 1,25(OH)2 D3 on EMT in the presence of IS. RESULTS: Pretreatment with 1,25(OH)2 D3 inhibited the IS-induced EMT-associated protein expression in HK-2 cells. IS induced the phosphorylation of Akt (S473) and β-catenin (S552) and subsequently increased the nuclear accumulation of β-catenin. Pretreatment with 1,25(OH)2 D3 and LY294002 (phosphoinositide 3-kinase [PIK3] inhibitor) significantly inhibited the IS-induced phosphorylation of Akt and β-catenin, nuclear β-catenin accumulation, and EMT-associated protein expression. CONCLUSIONS: Results from the present study revealed that the anti-EMT effect of 1,25(OH)2 D3 is likely through inhibition of the PI3K/Akt/β-catenin pathway, which leads to down-regulation of IS-driven EMT-associated protein expression in HK-2 human renal tubular epithelial cells. SN - 1873-1244 UR - https://www.unboundmedicine.com/medline/citation/31536856/1,25(OH)2_D3_attenuates_indoxyl_sulfate-induced_epithelial-to-mesenchymal_cell_transition_via_inactivation_of_PI3K/Akt/β-catenin_signaling_in_renal_tubular_epithelial_cells L2 - https://linkinghub.elsevier.com/retrieve/pii/S0899-9007(19)30113-3 DB - PRIME DP - Unbound Medicine ER -