Meloxicam fails to augment the reno-protective effects of soluble epoxide hydrolase inhibition in streptozotocin-induced diabetic rats via increased 20-HETE levels

• Published in: Prostaglandins & other lipid mediators 2017-09, Vol.132, p.3-11
• Main Authors: Katary, Mohamed M., Pye, Chelsey, Elmarakby, Ahmed A.
• Format: Article
• Language: English
• Subjects: 20-HETE; Animals; Blood Glucose - metabolism; Blood Pressure - drug effects; Body Weight - drug effects; Cytochrome P-450 Enzyme System - metabolism; Cytoprotection - drug effects; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - physiopathology; Drug Synergism; Enzyme Inhibitors - pharmacology; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - chemistry; Gene Expression Regulation, Enzymologic - drug effects; Hydroxyeicosatetraenoic Acids - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Meloxicam; Rats; Rats, Sprague-Dawley; Renal injury; Solubility; Sprague dawley rats; Streptozotocin; t-AUCB; Thiazines - pharmacology; Thiazoles - pharmacology
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2016.08.004

The pro-inflammatory cyclooxygenase (COX)-derived prostaglandins and the anti-inflammatory cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) play an important role in the regulation of renal injury. The current study examined whether COX inhibition augments the reno-protective effects of increased EETs levels via inhibiting EETs degradation by soluble epoxide hydrolase (sEH) in diabetic rats. Streptozotocin (50mg/kg, i.v) was used to induce diabetes in male Sprague Dawley rats. Rats were then divided into 5 groups (n=6-8); control non diabetic, diabetic, diabetic treated with the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), diabetic treated with the COX inhibitor meloxicam and diabetic treated with meloxicam plus t-AUCB for 2 months. Glomerular albumin permeability and urinary albumin and nephrin excretion levels were significantly elevated in diabetic rats together with decreased glomerular α3 integrin and nephrin expression levels. Inhibition of sEH reduced glomerular albumin permeability, albumin and nephrin excretion levels and restored the decrease in glomerular α3 integrin and nephrin expression in diabetic rats. Meloxicam failed to reduce renal injury or even to synergize the reno-protective effects of sEH inhibition in diabetic rats. Furthermore, inhibition of sEH reduced the elevation in renal collagen deposition and urinary MCP-1 excretion levels together with a reduction in the number of renal TUNEL positive cells in diabetic vs. control rats (P