Luo_2021_J.Biol.Chem__100667

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 trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was used to treat mice (1 mg/kg/d) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium-glucose cotransporter 2 (SGLT2) were markedly upregulated in the kidneys of mice fed a 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 knock-down or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the IKKalpha/beta/NF-kappaB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by a HF-HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression due to inactivation of the IKKalpha/beta/NF-kappaB-induced inflammatory response.