Estradiol Prevents High Glucose-Induced \u03b2-cell Apoptosis by Decreased BTG2 Expression

Suwattanee Kooptiwut,Mutita Junking,Namoiy Semprasert,Suchada Kaewin,Pa-Thai Yenchitsomanus,Kanchana Suksri,Jatuporn Sujjitjoon

doi:10.1038/s41598-018-30698-x

Suwattanee Kooptiwut, Mutita Junking + Show 5 more

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https://doi.org/10.1038/s41598-018-30698-x

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Journal: Scientific Reports	Publication Date: Aug 16, 2018
Citations: 24	License type: open-access

Affiliation: Siriraj Hospital, Mahidol University

Abstract

Hyperglycemia stimulates several pathways to induce pancreatic β-cell apoptosis. In our previous study by mRNA analysis, we demonstrated that B-cell translocation gene 2 (BTG2) expression was up-regulated in INS-1 cells cultured under high glucose conditions, but this effect was reversed by estrogen. In the present study, we demonstrated that BTG2 mRNA and protein expressions in both INS-1 cells and mouse pancreatic islets increased under high glucose conditions compared to those cultured under basal glucose conditions, while in the presence of estrogen, the BTG2 mRNA and protein expressions decreased. SiRNA-BTG2 significantly reduced cell apoptosis, cleaved-caspase 3, and Bax, compared to the siRNA-control in INS-1 cultured under high glucose conditions. We further demonstrated that BTG2 promoter activity was activated under high glucose conditions whereas estrogen significantly reduced it. The effects of estrogen on BTG2 expression were inhibited by estrogen receptor inhibitors. Also, under high glucose conditions, p53 and Bax mRNA and protein expressions increased, but they decreased in the presence of estrogen. Again, the effect of estrogen on p53 and Bax expression was inhibited by estrogen receptor inhibitors. Taken together, this study demonstrates that estrogen reduces pancreatic β-cell apoptosis under high glucose conditions via suppression of BTG2, p53, and Bax expressions.

Highlights

B-cell translocation gene 2 (BTG2) is known as pheochromocytoma cell 3 (PC3) in the rat and tetradecanoyl phorbol acetate-inducible sequence 21 (TIS21) in the mouse[5]
INS-1 cells cultured in a high glucose medium with 10−8 M 17-β estradiol significantly reduced the cleaved-caspase 3, suggesting that estrogen increased viable cells when the cells were cultured in high glucose (Fig. 1A)
In our preliminary study by mRNA analysis using the RT2 PCR array, the results showed that high glucose conditions increased BTG2 mRNA expression, Figure 3

Summary

Introduction

BTG2 is known as pheochromocytoma cell 3 (PC3) in the rat and tetradecanoyl phorbol acetate-inducible sequence 21 (TIS21) in the mouse[5]. High-glucose-regulated BTG2 expression has not been studied. Estrogens protected pancreatic β-cell from oxidative stress-induced apoptosis[16,19,20] and gluco-lipotoxicity[21] in mouse and human islets and protect survival of human islets transplanted in diabetic mice in vivo[22]. A previous study from our group demonstrated that estrogen protects against high glucose-induced pancreatic β-cell apoptosis via reduction of endoplasmic reticulum (ER) stress and oxidative stress[23]. The effect of estrogen on regulated BTG2 expression is still unrevealed in pancreatic β-cells. We hypothesized that estradiol protects pancreatic β-cell apoptosis against glucotoxicity via BTG2 suppression. This study aimed to examine whether or not estradiol suppresses BTG2 expression to prevent high-glucose-induced pancreatic β-cell apoptosis

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