Inhibition of the Soluble Epoxide Hydrolase Promotes Albuminuria in Mice with Progressive Renal Disease (original) (raw)
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Cytochrome P450 eicosanoids in hypertension and renal disease
Current opinion in nephrology and hypertension, 2015
Cytochrome (CYP) P450 metabolites of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) contribute to the regulation of renal tubular and vascular function. This review highlights the results of the recent genetic studies in humans and rodent models, indicating that these eicosanoids participate in the control of blood pressure (BP), chronic kidney disease (CKD), renal ischemia-reperfusion injury (IRI) and polycystic kidney disease (PKD). Endogenous 20-HETE has been reported to play an essential role in the myogenic and tubuloglomerular feedback responses in the afferent arteriole, and a deficiency of 20-HETE contributes to the development of hypertension and renal injury in Dahl S rats. Mutations in CYP4A11 and CYP4F2 have been linked to elevated BP in humans. EETs have been shown to regulate epithelial sodium channel in the collecting duct, lower BP and have renoprotective properties. 20-HETE also opposes the development of CKD and IRI...
Autonomic and Autacoid Pharmacology, 2009
Recent studies indicate that in the kidney arachidonic acid (AA) is metabolized by cytochrome P450 (CYP450) enzymes to produce epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acids (DiHETEs), and 19-and 20-hydroxyeicosatetrienoic acids (19-and 20-HETE). CYP450 metabolites of AA play a major role in the regulation of renal vascular tone, tubuloglomerular feedback (TGF), and sodium transport w1,2x. Enzymes of the CYP450 4A and 4F families catalyse the formation of 20-HETE. CYP450 4A mRNA and protein are expressed in the renal arterioles, glomerulus, proximal tubule (PT), cortical and medullary thick ascending limb of the loop of Henle (TALH), and in the pericytes surrounding vasa recta capillaries w2,3x. The renal arterioles, PTs, and glomeruli avidly produce 20-HETE, EETs, and DiHETEs when incubated with AA, while in the TALH, 20-HETE is the primary metabolite of AA w2x.
Cardiovascular Pharmacology: Open Access
Background/Aims: Cardiovascular events are common in patients with renocardiac syndrome. A direct link between endothelial dysfunction and increased cardiovascular events has not been established for this syndrome; however, a causal role could be attributed to modulations of Cytochrome P450-mediated (CYP450) eicosanoid metabolites including Epoxyeicosatrienoic (EETs), Dihydroxyeicosatrienoic (DHET) and 20-Hydroxyeicosatetraenoic acids (20-HETE). In this study we investigated inter-organ variations in CYP450-mediated eicosanoids in key organs from dogs with renal insufficiency. Methods: Renal insufficiency was induced by two-stage subtotal nephrectomy (SNx). Biochemical markers (serum creatinine, blood urea nitrogen) and cardiac hemodynamics were measured weekly. After 5 weeks, arachidonic acid CYP450-metabolites in heart, remnant kidney and liver biopsies were analyzed. Results: Serum creatinine and blood urea nitrogen were significantly higher in the SNx group (versus timematched sham controls); hematocrit, body weight and creatinine clearance were significantly reduced. The lymphocyte:monocyte ratio, a biomarker of vascular risk, was lower (p=NS) in SNx dogs. Cardiac hemodynamics were similar for both groups. Cardiac levels of 20-HETE were markedly lower (p=0.014) in SNx dogs; however, 14, 15-DHET, a biomarker of soluble epoxide hydrolase levels were unchanged. The 20-HETE/14, 15-DHET ratio was lower in these dogs (p=0.003) and could help to explain a loss of autoregulation in this experimental model. In kidney and liver biopsies from SNx dogs 20-HETE tended to be higher and 14, 15-DHET lower (p=NS) versus time-matched controls; no change was observed for 20-HETE/14, 15-DHET. Conclusion: A marked reduction of cardiac 20-HETE and 20-HETE/14, 15-DHET levels occurred in dogs with kidney injury but no change in these CYP450-metabolites was observed in kidney or liver biopsies. As such, kidney injury appears to trigger significant alterations in CYP450-metabolites that may initiate endothelial dysfunction and vascular inflammation even in distant organs. Manipulating these pathways may eventually constitute a potential pharmacologic target to limit vessel dysfunction in the setting of renocardiac syndrome.
Cytochrome P450, the arachidonic acid cascade, and hypertension: new vistas for an old enzyme system
The FASEB Journal, 1996
In the cytochromes P450 series, this review is the first of four articles addressing function and regulation of forms of cytochromes P450 involved in endogenous substrate metabolism. The arachidonic acid cascade leading to eicosinoids with strong vasoactive properties involves microsomal P450s. Capdevila and colleagues have pioneered study of the role of these P450 metabolites and in this review describe the biochemical characteristics of P450 arachidonic acid monooxygenases in rat kidney, which are found to be members of different CYP gene families. The functional significance of these enzymes and their products is described with particular attention to vasoactive properties and effects on ion transport. Study of renal P450 arachidonic acid monooxygenases indicates that their products significantly affect the physiological mechanisms that control fluid volume and composition. Studies in experimental models of hypertension indicate the importance of these enzymes in certain aspects of this complex disease.
Elevated lipoxygenase and cytochrome P450 products predict progression of chronic kidney disease
Nephrology Dialysis Transplantation, 2018
BackgroundThe clinical relevance of arachidonic acid (AA) metabolites in chronic kidney disease (CKD) progression is poorly understood. We aimed to compare the concentrations of 85 enzymatic pathway products of AA metabolism in patients with CKD who progressed to end-stage kidney disease (ESKD) versus patients who did not in a subcohort of Chronic Renal Insufficiency Cohort (CRIC) and to estimate the risk of CKD progression and major cardiovascular events by levels of AA metabolites and their link to enzymatic metabolic pathways.MethodsA total 123 patients in the CRIC study who progressed to ESKD were frequency matched with 177 nonprogressors and serum eicosanoids were quantified by mass spectrometry. We applied serum collected at patients’ Year 1 visit and outcome of progression to ESKD was ascertained over the next 10 years. We used logistic regression models for risk estimation.ResultsBaseline 15-hydroxyeicosatetraenoate (HETE) and 20-HETE levels were significantly elevated in progressors (false discovery rate Q ≤ 0.026). The median 20-HETE level was 7.6 pmol/mL [interquartile range (IQR) 4.2–14.5] in progressors and 5.4 pmol/mL (IQR 2.8–9.4) in nonprogressors (P < 0.001). In an adjusted model, only 20-HETE independently predicted CKD progression. Each 1 standard deviation increase in 20-HETE was independently associated with 1.45-fold higher odds of progression (95% confidence interval 1.07–1.95; P = 0.017). Principal components of lipoxygenase (LOX) and cytochrome P450 (CYP450) pathways were independently associated with CKD progression.ConclusionsWe found higher odds of CKD progression associated with higher 20-HETE, LOX and CYP450 metabolic pathways. These alterations precede CKD progression and may serve as targets for interventions aimed at halting progression.
AJP: Renal Physiology, 2005
This study compared the renal metabolism of arachidonic acid in Brattleboro (BB) (vasopressin deficient) and Long-Evans (LE) control rats and the effects of a cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) on renal function in these animals. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical and outer medullary microsomes was significantly greater in BB than in LE rats (155 ± 16 vs. 92 ± 13 and 59 ± 7 vs. 33 ± 3 pmol·min−1·mg protein−1). Renal cortical epoxygenase activity was not different in these strains. The expression of CYP4A proteins was 58 and 78% higher in the renal cortex and outer medulla of BB than in LE rats. Chronic treatment of BB rats with a vasopressin type 2 receptor agonist for 1 wk normalized the renal production of 20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effect on renal function in LE rats. However, urine flow increased by 54% and urine osmolarity decreased by 33% in BB rats treat...
American journal of hypertension, 1997
Arachidonic acid metabolism through the cytochrome P450-dependent monooxygenase system has been the subject of considerable research interest over the last several years. This article reviews the biological actions of the metabolites generated through this pathway and explores their role in the regulation of renal function and systemic blood pressure. Arachidonic acid is metabolized by the cytochrome P450-dependent monooxygenase system in three ways: epoxidation, resulting in the formation of 5,6-, 8,9-, 11,12-, 14,15-epoxyeicosatrienoic acids; allylic oxidation, resulting in the formation of 5,8,9,11,12,15-hydroxyeicosatetraenoic acids (HETE); and hydroxylation, resulting in the formation of 19,20-HETEs and 20-carboxyl arachidonic acid. Elements of this pathway have been localized in the kidney and several extrarenal sites. Vasodilation, vasoconstriction, inhibition of Na+,K+-ATPase, inhibition of ion transport and modulation of cell growth have been some of the diverse physiologic...
Prostaglandins & Other Lipid Mediators, 2015
This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10 mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFκB inhibitor IκB and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal