EET enhances renal function in obese mice resulting in restoration of HO-1-Mfn1/2 signaling, and decrease in hypertension through inhibition of sodium chloride co-transporter

• Published in: Prostaglandins & other lipid mediators Vol. 137; pp. 30 - 39
• Main Authors: Schragenheim, Joseph, Bellner, Lars, Cao, Jian, Singh, Shailendra P., Bamshad, David, McClung, John A., Maayan, Omri, Meissner, Aliza, Grant, Ilana, Stier, Charles T., Abraham, Nader G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2018
• Subjects: 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Epithelial sodium channel; Epithelial Sodium Channels - metabolism; GTP Phosphohydrolases - metabolism; Heme Oxygenase-1 - metabolism; Hypertension; Hypertension - drug therapy; Hypertension - metabolism; Insulin sensitivity; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney Diseases - drug therapy; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Diseases - physiopathology; Membrane Proteins - metabolism; Mice; Mitochondrial function; Obesity; Obesity - drug therapy; Obesity - metabolism; Obesity - pathology; Obesity - physiopathology; Signal Transduction - drug effects; Sodium excretion; Sodium-chloride cotransporter; Hypertension; Sodium excretion; Obesity; Epithelial sodium channel; Mitochondrial function; Insulin sensitivity; Sodium-chloride cotransporter
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2018.05.008

•EET-agonist reduces sodium retention and decreased both NCC and ENaC proteins.•EET agonist improvement of insulin receptor phosphorylation and decreased perirenal fat and inflammatory adipokines.•EET-Agonist reprograming of the perirenal fat to a brite phenotype.•EET-agonist intervention mitochondrial and thermogenic gene levels.
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.