Epoxyeicosatrienoic acids improve glucose homeostasis by preventing NF-κB-mediated transcription of SGLT2 in renal tubular epithelial cells
Epoxyeicosatrienoic acids improve glucose homeostasis by preventing NF-κB-mediated transcription of SGLT2 in renal tubular epithelial cells
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环氧二十碳三烯酸通过阻止肾小管上皮细胞中 NF-κB 介导的 SGLT2 转录来改善葡萄糖稳态
DOI：
10.1016/j.mce.2020.111149
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发表时间：
2021-01-08
影响因子：
4.1
通讯作者：
Xu, Xizhen
中科院分区：
文献类型：
--
作者：
Fu, Menglu;Yu, Jing;Xu, Xizhen
研究表明，环氧二十碳三烯酸（epoxyeicosatrienoicacids，ESTs）可调节葡萄糖稳态，但具体机制尚需进一步探讨。钠-葡萄糖协同转运蛋白2（SGLT 2）在糖尿病肾脏中高度表达，其进一步促进葡萄糖的肾脏重吸收以响应糖尿病的高血糖状态。在此，是否Eclampin可以作为SGLT 2的潜在抑制剂来调节糖尿病状态下的葡萄糖稳态需要阐明。我们的研究表明，在糖尿病小鼠中，Eglutamine通过肾小管上皮细胞减弱葡萄糖重吸收，这部分解释了Eglutamine对葡萄糖稳态的有益作用。此外，14，15-EET抑制糖尿病肾脏和肾小管上皮细胞中SGLT 2的表达。此外，用BAY 11-7082抑制NF-κ B可降低胰岛素诱导的SGLT 2表达，而NF-κ B过表达可逆转上述效应。此外，14，15-EET通过灭活NF-κ B减弱SGLT 2表达。从机制上讲，14，15-EET在-1821/1812 P65结合位点减弱NF-κ B介导的SGLT 2转录。这些结果表明，依地平通过阻止NF-κ B介导的SGLT 2在肾小管上皮细胞中的转录来改善葡萄糖稳态，为胰岛素抵抗和糖尿病提供了独特的治疗策略。
Studies have shown that epoxyeicosatrienoic acids (EETs) can regulate glucose homeostasis, but the specific mechanisms need further exploration. The sodium-glucose co-transporter 2 (SGLT2) is highly expressed in diabetic kidneys, which further promotes renal reabsorption of glucose to respond to the hyperglycemic state of diabetes. Herein, whether EETs can be a latent inhibitor of SGLT2 to regulate glucose homeostasis in diabetic state needs to be elucidated. Our study demonstrated that EETs attenuated the glucose reabsorption via renal tubular epithelial cells in diabetic mice, which partly accounted for the beneficial effects of EETs on glucose homeostasis. Moreover, 14,15-EET suppressed SGLT2 expression in both diabetic kidney and renal tubular epithelial cells. Further, inhibition of NF-kappa B with BAY 11-7082 decreased insulin-induced SGLT2 expression while NF-kappa B overexpression reversed the above effects. In addition, 14,15-EET attenuated SGLT2 expression via inactivating NF-kappa B. Mechanistically, 14,15-EET attenuated NF-kappa B mediated SGLT2 transcription at the -1821/1812 P65-binding site. These results showed that EETs ameliorated glucose homeostasis via preventing NF-kappa B-mediated transcription of SGLT2 in renal tubular epithelial cells, providing a unique therapeutic strategy for insulin resistance and diabetes.