1,25(OH) 2 D 3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells

Li-Chien Chang, Hai-Lun Sun, Chia-Han Tsai, Chia-Wen Kuo, Kai-Li Liu, Chong-Kuei Lii, Chin-Shiu Huang, Chien-Chun Li
Nutrition 2020, 69: 110554

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.

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