Abstract 90: Epoxyeicosatrienoic Acids Activation of Peroxisome Proliferator-activated Receptor Gamma Contributes to the Reduction in Glomerular Inflammation in Mice Model of Metabolic Syndrome
Studies support a link between the development of insulin resistance and the progression of renal inflammation in metabolic syndrome. Inhibition of soluble epoxide hydrolase (sEH) increases EETs levels and improves insulin signaling in type 2 diabetes, yet the molecular reno-protective mechanism (s) of EETs is/are not clearly understood. We hypothesize that decreased EETs levels mediate glomerular injury in type 2 diabetes through PPAR-γ induction. Obese db/db mice were treated with the sEH inhibitor t-AUCB (10 mg/L) alone or in combination with the PPAR-γ antagonist GW9662 (10 mg/kg ip, twice weekly) for 12 weeks. Renal EETs levels were significantly lesser in db/db mice compared to lean counterpart (100±6 vs. 162±18 ng/mg) although there was no difference in renal sEH expression between lean and obese mice. Inhibition of sEH with t-AUCB increased EETs levels in db/db mice (176±20 ng/mg). Obese db/db mice showed podocyte detachment from glomerular basement membrane and foot process effacement in glomerular tufts relative to lean and this effect was prevented with t-AUCB. Obese db/db mice also had a significantly lesser glomerular nephrin expression and higher albuminuria and nephrinuria than lean and t-AUCB treatment prevented these changes (p<0.05). Renal PPAR-γ activity and expression decreased in db/db mice together with elevation of renal p65-NFκB compared to lean mice and these changes were prevented with t-AUCB treatment. Co-administration of GW9662 with t-AUCB reversed t-AUCB’s ability to lower albuminuria and to restore glomerular nephrin expression and podocyte loss in db/db mice. Co-administration of GW9662 also blocked the ability of t-AUCB to lower T-cell infiltration, IL-17 expression and renal p-65NFκB activation in db/db mice. In conclusion, our data suggest that increased EETs levels via the inhibition of sEH in db/db mice activate PPAR-γ which in turn inhibits renal NFκB activation and reduce glomerular injury in db/db mice.
- © 2013 by American Heart Association, Inc.