Fenofibrate Treatment of Diabetic Rats Reduces Nitrosative Stress, Renal Cyclooxygenase-2 Expression, and Enhanced Renal Prostaglandin Release

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 ␣ 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 agematched control rats (n ϭ 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) E 2 in response to AA was enhanced in the diabetic rat kidney compared with control (4.8 Ϯ 0.7 versus 1.9 Ϯ 0.7 ng/min) and reduced by fenofibrate to 0.6 Ϯ 0.2 ng/min. A similar pattern was obtained for AA-stimulated release of 6-ketoPGF 1␣ . 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 Ϯ 0.4 versus 1.15 Ϯ 0.1 ml/min for control, and reduced by fenofibrate treatment to 1.87 Ϯ 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.

Sensory Neurons and Schwann Cells Respond to Oxidative Stress by Increasing Antioxidant Defense Mechanisms

“…Recent clinical trials demonstrated that fenofibrate also may provide therapeutic protection against retinopathy (1). In type 2 diabetic rats, fenofibrate decreased evidence of nephropathy (11). Taken with our present study, fenofibrate appears to be a strong candidate for the prevention of macro-and microvascular complications in diabetes.…”

Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats

“…We confirmed the increase in renal COX-2 in the diabetic rat and showed an association with enhanced prostaglandin release from the perfused kidney challenged with AA, which serves as an index of COX activity but does not distinguish the COX isoforms (24). Nonetheless, our studies have shown that interventions that prevent the upregulation of renal COX-2 in the diabetic rat are, for the most part, associated with a reduction of the exaggerated renal release of prostaglandins in response to AA, suggesting that increased COX-2 expression/activity contributes to the enhanced prostaglandin production in the diabetic rat (2,3,18). Subsequently, the upregulation of renal COX-2 was linked to elevated glomerular filtration rate (GFR) using inhibitors of COX-2 (17).…”

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy

“…All groups were treated orally via gavage daily for 12 weeks [30]. A subtherapeutic dose of insulin (2- 3 U) was given day after day in order to maintain body weight (BW) and decrease the mortality rate [32].…”

“…Sixty male Wistar rats were included in this study and divided randomly into four groups (15 rats each) as follows: group 1: nondiabetic control rats that received drug vehicle (normal saline); group 2: STZ-diabetic control rats that received drug vehicle (normal saline); group 3: diabetic rats treated with fenofibrate (100 mg/kg/day) suspended in 0.5% w/v of carboxymethyl cellulose [30]; group 4: diabetic rats treated with valsartan (15 mg/kg/day) dissolved in normal saline [31]. All groups were treated orally via gavage daily for 12 weeks [30].…”