Effect of Cilostazol on the Nephropathy of Streptozotocin-Induced Diabetic Rats

• Main Authors: Wen-Chin Lee, 李文欽
• Other Authors: 陳鴻震
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/38398148149987912037

博士 === 國立中興大學 === 生命科學系所 === 98 === Diabetic nephropathy is characterized as the progressive development of renal insufficiency in the setting of hyperglycemia is now the major single cause of end stage renal failure in many countries. Hyperglycemia activates the glycolytic pathway and induces ROS generation in renal tissue, then induces inflammatory response and activates profibrotic signals. The microscopic finding of diabetic nephropathy includes glomerular hypertrophy, mesangial matrix expansion, and glomerular basement membrane thickening. In the clinical observation, microalbuminuria is the typical presentation of early diabetic nephropathy. Cilostazol is a specific inhibitor of phosphodiesterase 3, which prevents platelet aggregation and dilates blood vessels via an increase in tissue cAMP levels. Cilostazol was reported that it lowered the albuminuria in streptozotocin-induced diabetic rats. It also found that cilostazol decreased the production of superoxide significantly in situ. But, as treating with cilostazol in streptozotocin induced diabetes, the relationship between improving oxidative stress and decreasing diabetic nephropathy has not been elucidated. We hypothesized that cilostazol administration in streptozotocin-induced diabetic rats may exert effects via improving oxidative stress, and the downstream signals, such as NF-κB, and TGF-β, thus ameliorate the early stage of diabetic nephropathy. Male Sprague-Dawley rats were used to induce diabetes mellitus by streptozotocin intraperitoneal injection. We fed the diabetic rats with cilostazol and compared them to the nontreated control group. The serum biochemistry, spot urine albumin/creatinine ratio, pathological change, oxidative stress parameters, and the expression of NF-κB, TGF-β in the kidneys were analyzed. Our results showed that cilostazol decreased urine albumin/creatinine ratio significantly in streptozotocin-induced diabetic rats. When compared the ROS activity in kidney tissues, it showed that cilostazol decreased MDA level, increased catalase activity and GSH level significantly in the kidney of diabetic rats. TGF-β and NF-κB were up-regulated in diabetic kidneys and were blunted by cilostazol. In addition, we used high glucose to induce ROS and treated with 10, 50, 100 μM of cilostazol in rat mesangial cells (RMCs). We found that the ROS generation was increased in high glucose condition and decreased by cilostazol. We also detected the activity of NADPH oxidase in the cell treated with high glucose accompanied by cilostazol. The results showed that cilostazol decreased the NADPH oxidase activity induced by high glucose. These results demonstrated that cilostazol inhibited ROS generation via inhibiting the activity of NADPH oxidase. Besides, we also tested the expressions of NF-κB p65 and TGF-β. We found that the NF-κB p65 and TGF-β were both increased in high glucose condition, and decreased by cilostazol treatment. It is therefore suggested that cilostazol ameliorates early stage nephropathy via improving oxidative stress, and decrease the expression of NF-κB and TGF-β in streptozotocin-induced diabetic rats.