8-11-14-eicosatrienoic-acid and Kidney-Diseases

Biologically active epoxyeicosatrienoic acid (EET) regioisomers 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 after 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 preclinical 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 antiremodeling 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 preclinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Administration, Oral; Animals; Blood Pressure; Cardiovascular Diseases; Fatty Acids, Monounsaturated; Humans; Hypertension; Kidney Diseases; Muscle, Smooth, Vascular; Structure-Activity Relationship; Vasodilation

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antihypertensive Agents; Disease Models, Animal; Disease Progression; Endothelium, Vascular; Fatty Acids; Humans; Hypertension; Kidney Diseases; Mice; Rats

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Disease Models, Animal; Epoxide Hydrolases; Forecasting; Humans; Hypertension; Kidney; Kidney Diseases; Mice; Natriuresis; Potassium; Rats; Rats, Inbred Dahl; Sodium Chloride; Sodium Chloride, Dietary; Vasodilation; Water-Electrolyte Balance; Water-Electrolyte Imbalance

We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on renal and adipose tissue function, in addition to its vasodilatory action; it increases insulin sensitivity and inhibits inflammation. In an examination of the signaling mechanisms by which EET reduces renal and peri-renal fat function, we hypothesized that EET ameliorates obesity-induced renal dysfunction by improving sodium excretion, reducing the sodium-chloride cotransporter NCC, lowering blood pressure, and enhancing mitochondrial and thermogenic gene levels in PGC-1α dependent mice.. EET-agonist treatment normalized glucose metabolism, renal ENaC and NCC protein expression, urinary sodium excretion and blood pressure in obese (db/db) mice. A marked improvement in mitochondrial integrity, thermogenic genes, and PGC-1α-HO-1-adiponectin signaling occurred. Knockout of PGC-1α in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in sodium excretion, elevation of blood pressure and an increase in the pro-inflammatory adipokine nephroblastoma overexpressed gene (NOV). In the elucidation of the effects of EET on peri-renal adipose tissue, EET increased adiponectin, mitochondrial integrity, thermogenic genes and decreased NOV, i.e. "Browning' peri-renal adipose phenotype that occurs under high fat diets. Taken together, these data demonstrate a critical role of an EET agonist in the restoration of healthy adipose tissue with reduced release of inflammatory molecules, such as AngII and NOV, thereby preventing their detrimental impact on sodium absorption and NCC levels and the development of obesity-induced renal dysfunction.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Epithelial Sodium Channels; GTP Phosphohydrolases; Heme Oxygenase-1; Hypertension; Kidney; Kidney Diseases; Membrane Proteins; Mice; Obesity; Signal Transduction

Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40-80% along with a 50-70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50-90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.

Topics: 8,11,14-Eicosatrienoic Acid; Administration, Oral; Animals; Apoptosis; Blood Urea Nitrogen; Cell Line, Tumor; Cell Survival; Cisplatin; Creatinine; Cross-Linking Reagents; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Gene Expression; HEK293 Cells; HeLa Cells; Humans; Kidney; Kidney Diseases; Male; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase; Superoxide Dismutase-1; Vasodilator Agents

Cardiorenal syndromes were defined and classified recently, but the mechanism of chronic renocardiac syndrome remains disputed. Theories about chronic renocardiac syndrome cannot offer a convincing explanation for it. As a result, the current therapies of chronic renocardiac syndrome do not contribute to a satisfied prognosis. Epoxyeicosatrienoic acids, the products of arachidonic acid metabolized by cytochrome P450 enzymes, play an important role in the maintenance of renal hemodynamics, and regulation of renal, cardiac, and vascular function with antihypertensive and anti-inflammatory properties. It is well documented that down-regulation of epoxyeicosatrienoic acids might be involved in alterations in various pathophysiological states, including hypertension, uremia and hepatorenal syndrome. Likewise, epoxyeicosatrienoic acids were reduced in heart failure and renal dysfunction. This leads to the proposed hypothesis that epoxyeicosatrienoic acids down-regulation may be the novel mechanism of chronic renocardiac syndrome. These findings suggest that manipulation of epoxyeicosatrienoic acid levels could be a novel pharmacological therapy strategy for chronic renocardiac syndrome.

Topics: 8,11,14-Eicosatrienoic Acid; Chronic Disease; Heart Diseases; Humans; Kidney Diseases; Syndrome

Cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolites are involved in the regulation of renal vascular tone and salt excretion. The epoxygenation product 11,12-epoxyeicosatrienoic acid (EET) is anti-inflammatory and inhibits nuclear factor-kappa B activation. We tested the hypothesis that the peroxisome proliferator-activated receptor-alpha-activator fenofibrate (Feno) induces CYP isoforms, AA hydroxylation, and epoxygenation activity, and protects against inflammatory organ damage. Double-transgenic rats (dTGRs) overexpressing human renin and angiotensinogen genes were treated with Feno. Feno normalized blood pressure, albuminuria, reduced nuclear factor-kappa B activity, and renal leukocyte infiltration. Renal epoxygenase activity was lower in dTGRs compared to nontransgenic rats. Feno strongly induced renal CYP2C23 protein and AA-epoxygenase activity under pathological and nonpathological conditions. In both cases, CYP2C23 was the major isoform responsible for 11,12-EET formation. Moreover, we describe a novel CYP2C23-dependent pathway leading to hydroxy-EETs (HEETs), which may serve as endogenous peroxisome proliferator-activated receptor-alpha activators. The capacity to produce HEETs via CYP2C23-dependent epoxygenation of 20-HETE and CYP4A-dependent hydroxylation of EETs was reduced in dTGR kidneys and induced by Feno. These results demonstrate that Feno protects against angiotensin II-induced renal damage and acts as inducer of CYP2C23-mediated epoxygenase activities. We propose that CYP-dependent EET/HEET production may serve as an anti-inflammatory control mechanism.

Topics: 8,11,14-Eicosatrienoic Acid; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Arachidonic Acid; Blotting, Western; Chromatography, Liquid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Fenofibrate; Humans; Hypertension; Hypolipidemic Agents; Immunohistochemistry; Kidney; Kidney Diseases; Mass Spectrometry; NF-kappa B; Polymerase Chain Reaction; Rats; Receptors, Cytoplasmic and Nuclear; Renin; Transcription Factors; Vasoconstrictor Agents