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    Autoimmune aspects of diabetes mellitus.

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    Title Page Fenofibrate treatment of diabetic rats reduces nitrosative stress, renal COX-2 expression and enhanced renal prostaglandin release. JPET #129197 2 Running Title Page Running title: Fenofibrate and renal COX-2 in diabetes. Abbreviations AA -arac

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    Abstract Renal COX-2 expression is increased in the diabetic rat and has been linked to increased GFR and renal injury. Our studies indicate that oxidative stress in the form of peroxynitrite (ONOO) may be the stimulus for induction of COX-2. In this study, we addressed the effects of a PPARα agonist on renal COX-2 expression as fibrates exert renal protective effects. 48h after the induction of diabetes with streptozotocin in male Wistar rats, fenofibrate treatment (100mg/kg/day) was started and the effects compared to untreated diabetic rats and treated and untreated age-matched control rats (n=5 per group). After 12-14 weeks of treatment, the right kidney was perfused to determine prostaglandin release in response to arachidonic acid (AA) and the left kidney used to examine the expression of COX-2 and nitrotyrosine, an index of ONOO formation. Release of PGE 2 in response to AA was enhanced in the diabetic rat kidney compared to control (4.8±0.7 vs 1.9±0.7ng/min) and reduced by fenofibrate to 0.6±0.2ng/min. A similar pattern was obtained for AA-stimulated release of 6-ketoPGF 1α . The effects of fenofibrate were associated with reduced renal expression of COX-2 and nitrotyrosine in diabetic rats. We used creatinine clearance as an index of GFR, which was increased in the diabetic rat, 3.09±0.4 vs 1.15±0.1ml/min for control, and reduced by fenofibrate treatment to 1.87±0.3ml/min. These results show that fenofibrate treatment of diabetic rats decreases renal COX-2 expression, possibly by reducing nitrosative stress, and is associated with a reduction of the enhanced GFR
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