Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats

Abstract

SUMMARY The aim of the present study was to test the hypothesis that increasing kidney tissue epoxyeicosatrienoic acids (EETs) concentration by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH), would attenuate the progression of chronic kidney disease (CKD). Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin II (ANG II)-dependent hypertension. sEH was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/l of drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. c-AUCB treatment when applied in TGR subjected to 5/6 NX improved the rats’ survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury, and reduced the glomerular volume, All these organ-protective actions were associated with normalization of the intrarenal EETs/DHETEs ratio, an index of availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent alterations of increased intrarenal ANG II content. Taken together, these results show that, first, 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of ANG II-dependent hypertension. Second, restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions.

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

“…Significant hypertrophy occurs in several models of hypertension including the ANG II, 5/6 nephrectomy, and salt-sensitive hypertension models (3,23,17,30). Indeed, the concentration of ANG II in Bowman's space has been shown to be 1,000-fold higher than in the systemic circulation (36).…”

“…In this study, we show that ANG II-induced glomerular hypertrophy was independent of blood pressure or hormonal status, suggesting a local role for ANG II in modifying renal architecture, separate from changes in blood pressure. Indeed, angiotensin receptor blocker administration in male Ren-2 transgenic rats can partially prevent glomerular volume expansion in the 5/6 nephrectomy model of hypertension (17), while the combination therapy of a calcium channel blocker (azelnidipine) and an angiotensin receptor blocker (olmesartan) given to male saltsensitive rats reduces mean glomerular area to a greater degree than when either is given alone (30). Interestingly, blood pressures in the treatment groups were also reduced, making it difficult to determine whether the reduction in glomerular area was a result of blood pressure normalization or a function of angiotensin receptor antagonism.…”

“…We included an estrogen replacement group in the menopause study. We examined renal damage, including glomerular hypertrophy, to determine the role of sex hormones in this disease process (17,30).…”

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

“…Ang II promotes the latter cellular and molecular processes in NAFLD. TG (mRen2) 27 (Ren) rats as genetic model with excessive activity of the RAS [29] provides chronic endogenous high levels of tissue Ang II resulting in NAFLD progression, while AT1 blocker valsartan slows down steatosis and prevents inflammation, oxidative stress and fibrosis [30].…”

Inside epoxyeicosatrienoic acids and cardiovascular disease

“…Moreover, Kujal et al (2014) have recently shown that renin (Ren)-2 transgenic rats (TGR) after 5/6 renal mass reduction (i.e., a model of chronic kidney disease associated with Ang II-dependent hypertension), exhibit a profound deficiency of intrarenal availability of EETs, that was mitigated by the use of a sEH inhibitor [ cis -4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid c-(AUCB)]. This phenomenon was associated with renoprotective actions.…”