Inhibition of Soluble Epoxide Hydrolase for Renal Health

Abstract

A soluble epoxide hydrolase (sEH) mediates the metabolism of epoxy fatty acids to form the corresponding vicinal diols, which are usually inactive or less active than the epoxide substrates. The sEH enzyme presents in many organs, including but not limited to the liver, heart, spleen, lung, and kidney. Here we summarized the changes in the expression and activity of sEH in multiple renal diseases, such as acute kidney injury (AKI), diabetic nephrology (DN), chronic kidney diseases (CKD), hypertension-mediated renal damage, and other renal dysfunctions. We also discussed the pharmacologic effects and the underlying mechanisms of sEH inhibition by using an inhibitor of sEH and/or the generic deletion of sEH on multiple renal diseases. We believe that sEH is a potential therapeutic target for renal dysfunction although the target disease needs further investigation.

Inactivation of Cys674 in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase

“…Renal sEH is up-regulated in several hypertensive models, and inhibition of sEH lowers their BP (Liu, 2018), similar to our results in SKI mice. In this present report we have not investigated how SERCA2 may regulate sEH.…”

“…Compared with WT mice, the sEH of SKI mice increased and D 1 receptors decreased at the level of mRNA ( Figure S3), which were further supported at the level of protein in both renal cortex and primary RPT cells (Figure 4). sEH was mainly located in the RPT of kidney ( Figure S4; Liu, 2018) and this enzyme metabolizes epoxyeicosatrienoic acids to less active dihydroxyeicosatrienoic acids (He, Wang, Zhu, & Ai, 2016), and thus inhibits sodium excretion by enhancing the activity of Na + /K + -ATPase in RPT (Dos Santos, Dahly-Vernon, Hoagland, & Roman, 2004;Imig, 2000;Imig, 2004). On the contrary, activation of D 1 receptors promotes sodium excretion by inhibiting Na + /K + -ATPase in RPT (Zeng & Jose, 2011;Harris & Zhang, 2012).…”

Inhibition of soluble epoxide hydrolase attenuates renal tubular mitochondrial dysfunction and ER stress by restoring autophagic flux in diabetic nephropathy

“…sEH is a cytosolic enzyme that is widely distributed in the liver, heart and kidney, and it plays a pivotal role in the regulation of EET bioavailability 19 . Numerous studies have highlighted the potential benefits of sEH inhibition in the inflammatory response 20 , cardiovascular diseases 21 , non-alcoholic fatty liver 22 and renal disease [23][24][25] . A recent study demonstrated that the sEH inhibitor TUPS mitigated isoproterenol/angiotensin IIinduced cardiac hypertrophy by inhibiting mTOR signaling-mediated autophagy 26 , which indicated that sEH is associated with the regulation of autophagy.…”

<p>The Human Genetic Variants CYP2J2 rs2280275 and EPHX2 rs751141 and Risk of Diabetic Nephropathy in Egyptian Type 2 Diabetic Patients</p>

“…7 In many experimental studies, it was found that the inhibition of sEH had a renoprotective effect. 16,17 sEH is encoded by EPHX2 gene. 18 A common SNP in the EPHX2 gene is the functional rs751141 G/A polymorphism.…”