Objective 20-HETE promotes endothelial dysfunction by uncoupling eNOS, stimulating O2− production and reducing NO bioavailability. Moreover, 20-HETE-dependent vascular dysfunction and hypertension are associated with upregulation of the renin-angiotensin system (RAS). This study was undertaken to examine the contribution of RAS to 20-HETE actions in the vascular endothelium. Methods and Results In endothelial cells, 20-HETE induced ACE mRNA levels and increased ACE protein and activity by 2-3-fold; these effects were negated with addition of the 20-HETE antagonist, 20-HEDE. 20-HETE-induced ACE expression was PKC-independent and EGFR-tyrosine kinase- and IKKβ-dependent. ACE siRNA abolished 20-HETE-mediated inhibition of NO production and stimulation of O2− generation whereas AT1R siRNA attenuated these effects by 40%. 20-HETE-stimulated O2− production was negated by 20-HEDE and was attenuated by lisinopril and losartan. Importantly, 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries was also attenuated by lisinopril and losartan. Conclusions These results indicate that ACE and Ang II-AT1R activation contribute to 20-HETE-mediated endothelial cell and vascular dysfunction and further enforce the notion that excessive production of 20-HETE within the vasculature leads to hypertension via mechanisms that include the induction of endothelial ACE, thus perpetuating an increase in vascular Ang II which, together with 20-HETE, promotes vascular dysfunction.

Salt-sensitive hypertension leads to kidney injury. The Dahl salt-sensitive hypertensive rat (Dahl SS) is a model of salt-sensitive hypertension and progressive kidney injury. The current set of experimental studies evaluated the kidney protective potential of a novel epoxyecosatrienoic acid analog (EET-B) in Dahl SS hypertension. Dahl SS rats receiving high salt diet were treated with EET-B (10 mg/kg/d) or vehicle in drinking water for 14 days. Urine, plasma, and tissue samples were collected at the end of the treatment protocol to assess kidney injury, oxidative stress, inflammation, and endoplasmic reticulum stress. EET-B treatment in Dahl SS rats markedly reduced urinary albumin and nephrin excretion by 60–75% along with 30–60% reductions in glomerular injury, intra-tubular cast formation and kidney fibrosis without affecting blood pressure. In Dahl SS rats, EET-B treatment further caused marked reduction in oxidative stress with 25–30% decrease in kidney malondialdehyde content along with 42% increase of nitrate/nitrite and a 40% reduction of 8-isoprostane. EET-B treatment reduced urinary monocyte chemoattractant protein-1 by 50% along with a 40% reduction in macrophage infiltration in the kidney. Treatment with EET-B markedly reduced renal endoplasmic reticulum (ER) stress in Dahl SS rats with reduction in the kidney mRNA expressions and immunoreactivity of glucose regulatory protein 78 and C/EBP homologous protein. In summary, these experimental findings reveal that EET-B provides kidney protection in Dahl SS rats by reducing oxidative stress, inflammation and ER stress, and this protection was independent of reducing blood pressure.

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Oligosaccharides and glycoconjugates play an important role in biological processes. The use of these complex polymers as biocompatible materials for medicinal applications as well as therapeutic agents for the treatment of several diseases has attracted considerable interest. However, these investigations require large and pure amounts of glycostructures. Glucosamine is one of the major building blocks of these highly important glycoconjugates. Recently, considerable synthetic efforts have been devoted to improving stereoselective glycosylation. In this Focus review, the role of the amine protecting group in the outcome of the glucosamine glycosylation reaction is highlighted.