EET Enhances Renal Function in Obese Mice Resulting in Restoration of Mfn1/2 Signaling and a Decrease in Hypertension Through Inhibition of Sodium Chloride Co‐Transporter

Abstract

BackgroundObesity is a global epidemic and a major risk factor in the development of metabolic syndrome, diabetes and associated complications such as cardiovascular disease, kidney disease, hypertension, and neuropathies. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid generated by a super family of cytochrome P450 (CYP) monooxygenases and epoxygenases. Hypertension caused by chronic obesity in leptin receptor deficient mice, may be linked to mitochondrial dysfunction. Previously we and others have reported the beneficial effects of epoxyeicosatrienoic acid in renal and adipose tissue function, as well as its vasodilatory action, it increases insulin sensitivity and inhibits inflammation and reactive oxygen species (ROS). We hypothesized that EET attenuates obesity‐induced renal dysfunction by improving sodium excretion, reducing the sodium‐chloride cotransporter NCC, lowering blood pressure and increasing mitochondrial and thermogenic gene levels in PGC1α dependent mice.MethodsSixteen week‐old db/db mice were divided into 3 treatment groups for an additional 16‐wk experiment; Control, EET‐A 1.5 mg/100g BW i.p. 3x/week, and EET‐A‐Ln‐PGC‐1α shRNA (Ln‐PGC‐1 α shRNA suppressed PGC‐1α protein levels in renal tissue by >50%). After 16‐wks pf treatment oxygen consumption (VO2), visceral fat and fasting blood glucose levels were determined; urine was collected and renal tissues were harvested to measure: type 2 Na‐K‐Cl cotransporters (NKCC2), epithelial Na channels‐alpha subunit (ENac), NaCl cotransporters (NCC), PGC‐1α, HO‐1, and mitochondrial biogenesis markersResultsEET‐agonist normalized glucose metabolism, renal ENaC and NCC protein expression, urinary sodium excretion and blood pressure in obese mice. EET‐agonist improved mitochondrial integrity, thermogenic genes, and PGC1α‐HO‐1‐adiponectin signaling. Knockout of PGC1α 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 NOV. Effects of EET on perirenal adipose tissue included EET increased adiponectin, mitochondrial integrity and thermogenic genes and decreased NOV, i.e. ‘Browning’ perirenal adipose phenotype that occurs under high fat diets.ConclusionTreatment with an EET‐agonist led to the recruitment of PGC‐1α‐HO‐1, enhanced mitochondrial function, decreased perirenal fat‐derived NOV, and the downregulation of NCC channels resulting in a decrease in sodium retention in chronically obese mice. EET has the potential to serve as a powerful therapeutic agent in the treatment of obesity‐induced hypertension.Support or Funding InformationNational Institutes of Health grant (HL34300 to NGA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.