EFFECTS OF ROSUVASTATIN ON THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN STREPTOZOTOCIN-INDUCED DIABETIC RATS
Hanan H Hagar; Dana Bakheet, Nouf al-Otabi, and Raeesa AT Muhammed*
Departments of Pharmacology and *Anatomy, College of Medicine and Pharmacy, King Saud University, Riyadh, Saudi Arabia
Inflammatory process may be one of the critical factors that contribute to the development of diabetic nephropathy (DN). Statins as HMG-CoA reductase inhibitors have been shown to have anti-inflammatory effects independent of cholesterol-lowering action. The effects of two different doses of rosuvastatin (ROSV, 1 and 5 mg/kg/day, p.o.) on the progression of diabetic nephropathy in streptozotocin (STZ)-induced diabetic rats for eight weeks were investigated. Non diabetic and diabetic adult male Wistar rats were used. Diabetes was induced by a single intraperitoneal injection (i.p.) of STZ (55 mg/ kg). Three days after diabetes induction, to ensure hyperglycemia, rosuvastatin was administered orally once daily, for eight weeks to non diabetic and diabetic rats. Body weight, kidney body weight (K/BW) ratio, blood glucose level, lipid profile and kidney function indicators including urine volume, urinary total protein, urinary albumin excretion rate (UAER), serum creatinine, and glomerular filtration rate (GFR) were measured. Serum levels of nitrite /nitrate, inflammatory cytokine, intercellular adhesion molecule-1 (ICAM-1) and prosclerotic cytokine, transforming growth factor (TGF-β1) as well as the oxidative stress marker, 8-hydroxy-2'-deoxy guanosine (8-OHdG) in urine were assessed. Moreover, kidney histopathological examination and advanced glycosylation end products (AGE) immunoassaying were performed. Results of the present study indicated that induction of hyperglycaemia was associated with body weight loss, increased K/BW ratio, lipid profile abnormalities, increase in urine volume, total protein, UAER and serum creatinine level and a decline in GFR. Serum levels of nitrite/nitrate, ICAM-1, TGF-β1 and urinary 8-OHdG were elevated. The histological examination of renal tissues revealed mesangial expansion, excess collagen deposition and glomerular basement membrane thickening. Glomerulosclerosis was also evident by the increase in glomerulosclerosis index (GSI) and PAS staining. Treatment of diabetic rats with rosuvastatin corrected lipid profile abnormalities and significantly reduced diabetes-induced increase in serum creatinine level, UAER, serum levels of total nitrite/nitrate, ICAM-1, TGF-β1 and urinary 8-OHdG. Moreover, histopathological changes and AGE immunostaining-induced by diabetes were suppressed by rosuvastatin. On other hand, rosuvastatin did not affect the elevation of plasma glucose level and body weight loss. These results suggest that rosuvastatin exerts lipid lowering action and important anti-inflammatory effects through inhibition of oxidative stress and AGE accumulation. The pleotropic actions of rosuvastatin may offer potential benefits in addition to those associated with lipid lowering in the treatment of diabetic nephropathy.