Epoxyeicosatrienoic Acids, Hypertension, and Kidney Injury

Imig, John D.

doi:10.1161/hypertensionaha.114.03585

Cited by 71 publications

(60 citation statements)

References 79 publications

(157 reference statements)

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“…23 Recent experimental studies have shown that physiological active substances such as fibroblast growth factor 23 and epoxyeicosatrienoic acids not only regulate BP but also play an important role in regulation of cardiorenal syndrome. 24,25 These results indicate that the brain, heart, and kidney interact with each other, and that the underlying mechanisms are also involved in the regulation of BP; these findings thus contribute to the notion that hypertension plays an important role in cardiorenal-brain interactions.…”

mentioning

confidence: 69%

Higher Blood Pressure as a Risk Factor for Diseases Other Than Stroke and Ischemic Heart Disease

Kokubo

Iwashima

2015

Hypertension

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H ypertension is an established risk factor for stroke, ischemic heart disease, 1,2 and renal dysfunction. 3 The management and prevention of hypertension are important to the prevention of these diseases. Recent evidence has suggested that hypertension also plays a central role in the underlying pathophysiological condition or at prodromal stages before the development of these diseases. Accumulating evidence also indicates that hypertension seems to be linked with common noncardiovascular diseases including dementia, cancer, oral health diseases (OHDs), and osteoporosis. In this brief review, we organize the reported results about the associations between hypertension and these diseases, discussing mainly epidemiological surveys, with the goal of clarifying the relationships between these diseases and hypertension. Hypertension and Cardiorenal Diseases Atrial FibrillationAtrial fibrillation (AF) is one of the most common types of chronic arrhythmia and is a risk factor for ischemic stroke. 4 The Framingham Heart Study revealed that hypertension increases the risk of AF by factors of 1.5 for men and 1.4 for women.5 The Women's Health Study and a cohort study of Norwegian men showed that high-normal blood pressure (BP) was associated with incident AF.6,7 All of these cohort studies were conducted in Westerners, and these associations were also confirmed in a recent Japanese cohort study. 8 In that investigation, compared with normal BP and normal weight, systolic prehypertension with overweight was shown to be associated with an increased risk of incident AF (P for interaction=0.04). Arterial stiffness, left ventricular hypertrophy, and increased left atrial size are important mediators of the relationship between BP and incident AF. 9 Higher systolic BP (SBP) and overweight may mutually exacerbate left ventricular hypertrophy and hypertension, and consequently, they may synergistically increase the risk of AF. Chronic Kidney Disease and High BPChronic kidney disease (CKD) is characterized by a progressive decline in an individual's glomerular filtration rate over several decades, resulting in permanent kidney dysfunction. Hypertension is consistently demonstrated to be an independent risk factor for declining glomerular filtration rate and the progression of CKD, 10-12 partly because of activation of the renin-angiotensin-aldosterone system and sympathetic nervous system activation. A systematic review and meta-analysis of prospective cohort studies showed that prehypertension is associated with incident end-stage renal disease.3 Compared with a normal BP group, the prehypertensive group had a 1.59× increased risk of end-stage renal disease. Even normal BP increased the risk of end-stage renal disease; this association was accentuated by age, sex, and ethnicity and also varied depending on the study. In addition, a systematic meta-analysis showed that individual components of metabolic syndrome other than elevated BP (hazard ratio, 1.61; 95% confidence interval, 1.29-2.01) were also associated with the develo...

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mentioning

confidence: 69%

Higher Blood Pressure as a Risk Factor for Diseases Other Than Stroke and Ischemic Heart Disease

Kokubo

Iwashima

2015

Hypertension

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“…The therapeutic potential for manipulating EETs has been well recognized for the past decade with the development of sEH inhibitors that increase the EET to DHET ratio (31, 123). The promising biological actions of EETs in a number of pre-clinical disease models has led to interest in developing EET-based therapeutic strategies and inspired the development of sEH inhibitors (Figure 3).…”

Section: Therapeutic Application Of Orally Active Eet Agonists In Prementioning

confidence: 99%

Orally Active Epoxyeicosatrienoic Acid Analogs

Campbell

Imig

Schmitz

et al. 2017

Journal of Cardiovascular Pharmacology

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Biologically active epoxyeicosatrienoic acid regioisomers (EETs) are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size following ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance and reduce the renal injury. These actions of EETs emphasize their therapeutic potential. To minimize metabolic inactivation, 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates were developed. In pre-clinical rat models, a subset of agonist analogs, termed EET-A, EET-B and EET-C22, are orally active with good pharmacokinetic properties. These orally active EET agonists lower blood pressure and reduce cardiac and renal injury in spontaneous and angiotensin hypertension. Other beneficial cardiovascular actions include improved endothelial function and cardiac anti-remodeling actions. In rats, EET analogs effectively combat acute and chronic kidney disease including drug- and radiation-induced kidney damage, hypertension and cardiorenal syndrome kidney damage, and metabolic syndrome and diabetes nephropathy. The compelling pre-clinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.

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“…Of these, we will focus on the COX-generated compounds which are believed to be the most important for renal tubule–tubule signaling [2] although other arachidonic acid metabolites (e.g., epoxyeicosatrienoic acids or 20-hydroxyeicosatetraenoic acid derived from the P450 system) can alter epithelial sodium transport, glomerular hemodynamics, and vascular reactivity and have anti-inflammatory effects [72,73▪]. …”

Section: Prostaglandinsmentioning

confidence: 99%

Kidney tubules

Ferenbach

Bonventre

2016

Current Opinion in Nephrology and Hypertension

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Purpose of review The kidney mediates the excretion or conservation of water and electrolytes in the face of changing fluid and salt intake and losses. To ultrafilter and reabsorb the exact quantities of free water and salts to maintain euvolemia a range of endocrine, paracrine, and hormonal signaling systems have evolved linking the tubules, capillaries, glomeruli, arterioles, and other intrinsic cells of the kidney. Our understanding of these systems remains incomplete. Recent findings Recent work has provided new insights into the workings of the communication pathways between tubular segments and the glomeruli and vasculature, with novel therapeutic agents in development. Particular progress has also been made in the visualization of tubuloglomerular feedback. Summary The review summarizes our current understanding of pathway functions in health and disease, as well as future therapeutic options to protect the healthy and injured kidney.

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Epoxyeicosatrienoic Acids, Hypertension, and Kidney Injury

Cited by 71 publications

References 79 publications

Higher Blood Pressure as a Risk Factor for Diseases Other Than Stroke and Ischemic Heart Disease

Higher Blood Pressure as a Risk Factor for Diseases Other Than Stroke and Ischemic Heart Disease

Orally Active Epoxyeicosatrienoic Acid Analogs

Kidney tubules

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