Abstract P031: Cyclooxygenase Inhibition Does Not Augment Reno-protective Effect of Soluble Epoxide Hydrolase Inhibitor in Streptozotocin-induced Diabetic Rats
Cyclooxygenase (COX)-derived prostaglandins and cytochrome P450 epoxygenase/soluble epoxide hydrolase (sEH) derived epoxyeicosatrienoic acids (EETs) play important role in the regulation of vascular tone. The aim of this work is to examine whether COX inhibition exacerbates the reno-protective effects of increased EETs levels, via inhibiting EETs degradation by sEH using sEH inhibitor, in streptozotocin-induced type 1 diabetes. Diabetes was induced in 12 week old Sprague Dawley rats using streptozotocin (50 mg/kg, i.v). Rats were divided into 5 groups (n=6); control non diabetic, diabetic, diabetic treated with the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB, 10 mg/L in drinking water), diabetic treated with COX inhibitor meloxicam (5 mg/kg/day in drinking water) and diabetic treated with both inhibitors for two months. Inhibition of sEH reduced the elevation in proteinuria and creatinine clearance in diabetic rats (P less than 0.05) and meloxicam did not exacerbate t-AUCB effects. Glomerular permeability to albumin and albuminuria were elevated in diabetic rats and were reduced with t-AUCB treatment; however, meloxicam did not augment t-AUCB effects on reducing glomerular injury. Inhibition of sEH with t-AUCB also restored the decrease in glomerular integrin and nephrin expression levels in diabetic rats without synergestic effect from meloxicam. Renal collagen deposition and the inflammatory marker monocyte chemoattractant protein-1 (MCP-1) excretion levels were significantly elevated in diabetic rats and were reduced with t-AUCB treatment without further significant protective effects from meloxicam treatment. The number of TUNEL positive cells, a marker of apoptosis, was higher in the kidney sections from diabetic rats versus control (P less than 0.05), an effect that was significantly mitigated by t-AUCB treatment but not with meloxicam treatment. In conclusion, increasing EETs levels in type 1 diabetic rats, using sEH inhibition, reduced renal apoptosis, inflammation and injury whereas inhibition of COX failed to provide renal protection or to augment reno-protective effect of sEH inhibition in diabetic rats.
Author Disclosures: M.A. Katary: None. C. Pye: None. A.A. Elmarakby: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2015 by American Heart Association, Inc.