Abstract
Renal cyclooxygenase (COX)-2 expression is increased in the diabetic rat and has been linked to increased glomerular filtration rate (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 peroxisome proliferator-activated receptor α agonist on renal COX-2 expression as fibrates exert renal protective effects. Forty-eight hours after the induction of diabetes with streptozotocin in male Wistar rats, fenofibrate treatment (100 mg/kg/day) was started, and the effects were compared with untreated diabetic rats and treated and untreated age-matched control rats (n = 5 per group). After 12 to 14 weeks of treatment, the right kidney was perfused to determine prostaglandin release in response to arachidonic acid (AA), and the left kidney was used to examine the expression of COX-2 and nitrotyrosine, an index of ONOO formation. Release of prostaglandin (PG) E2 in response to AA was enhanced in the diabetic rat kidney compared with control (4.8 ± 0.7 versus 1.9 ± 0.7 ng/min) and reduced by fenofibrate to 0.6 ± 0.2 ng/min. A similar pattern was obtained for AA-stimulated release of 6-ketoPGF1α. 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 versus 1.15 ± 0.1 ml/min for control, and reduced by fenofibrate treatment to 1.87 ± 0.3 ml/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.
Footnotes
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This study was supported by the American Diabetes Association and by National Institutes of Health Grant RO1HL069061.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.129197.
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ABBREVIATIONS: AA, arachidonic acid; COX, cyclooxygenase; GFR, glomerular filtration rate; STZ, streptozotocin; NOS, nitric-oxide synthase; PPAR, peroxisome proliferator-activated receptor; NF, nuclear factor; PG, prostaglandin; iNOS, inducible nitric-oxide synthase.
- Received July 25, 2007.
- Accepted November 8, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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