Induction of Angiotensin-Converting Enzyme and Activation of the Renin–Angiotensin System Contribute to 20-Hydroxyeicosatetraenoic Acid–Mediated Endothelial Dysfunction

Journal of the American Society of Nephrology

et al. 2015

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In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetesmediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.

Section: Discussionmentioning

confidence: 98%

Section: Increased Collagen Deposition and Glomerular Basement Membramentioning

confidence: 99%

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

Gangadhariah

Luther

Journal of the American Society of Nephrology

et al. 2015

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“…Vascular ACE expression requires the use of both the somatic and germinal ACE promoter regions, and disruption in these locations results in changes to protein structure and localization (Bernstein et al, 2005;Shen et al, 2008). We have recently identified 20-hydroxyeicosatetraenoic acid (20-HETE) as a potent inducer of endothelial ACE (Cheng et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

20-HETE Activates the Transcription of Angiotensin-Converting Enzyme via Nuclear Factor- B Translocation and Promoter Binding

Journal of Pharmacology and Experimental Therapeutics

Shkolnik

Milhau

et al. 2015

Increased vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 arachidonic acid metabolite, promotes vascular dysfunction, injury, and hypertension that is dependent, in part, on the renin angiotensin system (RAS). We have shown that, in human microvascular endothelial cells, 20-HETE increases angiotensin-converting enzyme (ACE) mRNA, protein, and ACE activity via an epidermal growth factor receptor (EGFR)/ tyrosine kinase/mitogen-activated protein kinase (MAPK)/ inhibitor of kB kinase (IKK)b-mediated signaling pathway. In this work, we show that, similar to epidermal growth factor (EGF), 20-HETE (10 nM) activates EGFR by stimulating tyrosine phosphorylation; however, unlike 20-HETE, EGF does not induce ACE expression, and pretreatment with a neutralizing antibody against EGF does not prevent the 20-HETE-mediated ACE induction. Inhibition of nuclear factor kB (NF-kB) activation prevented the 4.58-fold (60.78; P , 0.05) 20-HETE-mediated induction of ACE. The 20-HETE increased NF-kB-binding activity in nuclear extracts and the activity of both the somatic and germinal ACE promoters by 4.37-fold (60.18; P , 0.05) and 2.53-fold (6 0.24; P , 0.05), respectively. The 20-HETE-stimulated ACE promoter activity was abrogated by the 20-HETE antagonist 20-hydroxy-6,15-eicosadienoic acid and by inhibitors of EGFR, MAPK, IKKb, and NF-kB activation. Sequence analysis demonstrated the presence of two and one putative NF-kB binding sites on the human somatic and germinal ACE promoters, respectively. Chromatin immunoprecipitation assay indicated that 20-HETE stimulates the translocation and subsequent binding of NF-kB to each of the putative binding sites (S1, 3.43 6 0.3-fold enrichment versus vehicle; S2, 3.72 6 0.68-fold enrichment versus vehicle; S3, 3.20 6 0.18-fold enrichment versus vehicle; P , 0.05). This is the first study to identify NF-kB as a transcriptional factor for ACE and to implicate a distinct EGFR/MAPK/IKK/NF-kB signaling cascade underlying 20-HETE-mediated transcriptional activation of ACE mRNA and stimulation of ACE activity.

“…Both share several characteristics, as each has been shown to promote constrictor stimuli, smooth muscle proliferation and migration, increases in proinflammatory cytokines and chemokines, production of reactive oxygen species, enhanced expression of adhesion molecules, and arterial remodeling in hypertension (4,21,25,34). Our recent study identified 20-HETE as a potent inducer of endothelial angiotensin-converting enzyme (ACE), a critical enzyme involved in the production of the ANG II (3,6,30), suggested a close functional crosstalk between these two autacoids in the regulation of blood pressure and vascular function. To this end, experimental models of hypertension that show increased vascular 20-HETE production, such as the spontaneously hypertensive rats (SHR) (7) and androgen-induced hypertension (27,35,37), are also ANG II-mediated.…”

mentioning

confidence: 99%

Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension

American Journal of Physiology-Regulatory, Integrative and Comp

Joseph

Shkolnik

et al. 2015

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Increased vascular 20-HETE is associated with hypertension and activation of the reninangiotensin system (RAS) through induction of vascular angiotensinconverting enzyme (ACE) expression. Cyp4a12tg mice, whose Cyp4a12-20-HETE synthase expression is under the control of a tetracycline (doxycycline, DOX) promoter, were used to assess the contribution of ACE/RAS to microvascular remodeling in 20-HETEdependent hypertension. Treatment of Cyp4a12tg mice with DOX increased systolic blood pressure (SBP; 136 Ϯ 2 vs. 102 Ϯ 1 mmHg; P Ͻ 0.05), and this increase was prevented by administration of 20-HEDGE, lisinopril, or losartan. DOX-induced hypertension was associated with microvascular dysfunction and remodeling of preglomerular microvessels, which was prevented by 20-HEDGE, a 20-HETE antagonist, yet only lessened, but not prevented, by lisinopril or losartan. In ACE 3/3 mice, which lack vascular endothelial ACE, administration of 5␣-dihydrotestosterone (DHT), a known inducer of 20-HETE production, increased SBP; however, the increase was about 50% of that in wild-type (WT) mice (151 Ϯ 1 vs. 126 Ϯ 1 mmHg). Losartan and 20-HEDGE prevented the DHT-induced increase in SBP in WT and ACE 3/3 mice. DHT treatment increased 20-HETE production and microvascular remodeling in WT and ACE 3/3 mice; however, remodeling was attenuated in the ACE 3/3 mice as opposed to WT mice (15.83 Ϯ 1.11 vs. 22.17 Ϯ 0.92 m; P Ͻ 0.05). 20-HEDGE prevented microvascular remodeling in WT and ACE 3/3 mice, while losartan had no effect on microvascular remodeling in ACE 3/3. Taken together, these results suggest that RAS contributes to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE-driven microvascular remodeling independent of blood pressure elevation does not fully rely on ACE activity in the vascular endothelium.20-HETE; angiotensin II; ACE; vascular remodeling; hypertension; angiotensin-converting enzyme 20-HETE IS THE -HYDROXYLATION product of arachidonic acid metabolism by enzymes of the cytochrome P-450 (CYP) 4A and 4F families. It has been recognized as an eicosanoid of the microcirculation with renal, cerebral, cardiac, and mesenteric arteries having been shown to be rich sources of 20-HETE. Its effects on vascular function are multifaceted and include stimulation of smooth muscle contractility, migration, and proliferation, as well as activation of endothelial cell dysfunction, angiogenesis, and inflammation (1, 2, 4, 21, 34, 36). Such effects could have significant implications with regard to the development of hypertension and its cardiovascular complications. Indeed, numerous studies in experimental models of hypertension have documented a close relationship between increased vascular production of 20-HETE and blood pressure elevation. Models of 20-HETE-driven hypertension also exhibit vascular injury that is exemplified by endothelial and vascular dysfunction (11,15,17,33,35).Vascular remodeling is both a product of and contributor to the development of hypertension. This process is promoted by a variety of stimuli...