Inhibition of soluble epoxide hydrolase alleviates insulin resistance and hypertension via downregulation of SGLT2 in the mouse kidney.
Inhibition of soluble epoxide hydrolase alleviates insulin resistance and hypertension via downregulation of SGLT2 in the mouse kidney.
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抑制可溶性环氧化物水解酶通过下调小鼠肾脏中的 SGLT2 减轻胰岛素抵抗和高血压
DOI：
10.1016/j.jbc.2021.100667
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Luo J;Hu S;Fu M;Luo L;Li Y;Li W;Cai Y;Dong R;Yang Y;Tu L;Xu X
环氧二十碳三烯酸(EET)对胰岛素抵抗和/或高血压有有益的作用。EETs很容易被可溶性环氧化物水解酶(SEH)转化为生物活性较低的二醇。然而，抑制sEH是否能改善胰岛素抵抗和高血压的并存，以及这种关系的潜在机制尚不清楚。在这项研究中，C57BL/6小鼠通过高脂高盐(HF-HS)饮食造成高血压和胰岛素抵抗。用促肾上腺皮质激素释放激素抑制剂1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)尿素(TPPU)给小鼠灌胃(1 mg/kg/d)8周，然后进行代谢参数分析。喂食HF-HS饲料的小鼠肾脏中sEH和钠-葡萄糖协同转运体2(SGLT2)的表达显著上调。我们发现，服用TPPU可提高肾脏EET水平，改善胰岛素抵抗，降低高血压。此外，TPPU治疗阻止了SGLT2的上调和相关的尿量增加以及尿糖和尿钠的排泄。重要的是，TPPU减轻了肾脏炎症。体外用人肾近端小管上皮细胞(HK-2细胞)进一步探讨其作用机制。我们观察到，14，15-EET或sEH的敲除或抑制通过抑制抑制的kappa B激酶α/β/NF-κB信号通路来阻止棕榈酸或氯化钠处理后SGLT2的上调。总而言之，TPPU抑制sEH可减轻由HF-HS饮食引起的小鼠胰岛素抵抗和高血压。尿糖和钠排泄的增加是由肾SGLT2的表达减少所介导的，因为抑制的kappa B激酶α/β/NF-κB诱导的炎症反应失活。
The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension and the underlying mechanisms of this relationship are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF–HS) diet. The sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), was used to treat mice (1 mg/kg/day) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium–glucose cotransporter 2 (SGLT2) was markedly upregulated in the kidneys of mice fed an HF–HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2 and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knockdown or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the inhibitory kappa B kinase α/β/NF-κB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by an HF–HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression because of inactivation of the inhibitory kappa B kinase α/β/NF-κB–induced inflammatory response.
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影响因子：
29
作者：
Baker RG;Hayden MS;Ghosh S
通讯作者：
Ghosh S
DOI：
10.1016/j.ecl.2013.09.005
发表时间：
2014-03
影响因子：
4.5
作者：
Lastra, Guido;Syed, Sofia;Kurukulasuriya, L. Romayne;Manrique, Camila;Sowers, James R.
通讯作者：
Sowers, James R.
DOI：
10.1111/j.1559-4564.2006.05513.x
发表时间：
2006-01-01
期刊：
Journal of the cardiometabolic syndrome
影响因子：
--
作者：
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通讯作者：
Stern, Naftali
DOI：
10.1152/ajpheart.00533.2009
发表时间：
2010-02-01
影响因子：
4.8
作者：
Merkel, Matthias J.;Liu, Lijuan;Van Winkle, Donna M.
通讯作者：
Van Winkle, Donna M.
DOI：
10.1161/hypertensionaha.110.162446
发表时间：
2011-05
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
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通讯作者：
Campbell NR