Background. Diabetic nephropathy is the major cause of end stage renal disease especially in developing countries. Reducing proteinuria is the mainstay of therapy in order to delay the progression of chronic kidney disease. Current therapeutic regimens provide only partial renoprotection, and a substantial number of patients who have proteinuria progress to end stage renal disease. Aim. The aim of this study was to evaluate the effects of pentoxifylline and diltiazem versus rosuvastatin on development and progression of nephropathy in streptozotocin induced diabetic rats and possible mechanisms of action. Materials and Methods. Eighty adult albino rats were randomly divided into eight groups: the first and second groups are normal control and diabetic control. Streptozotocin-induced type 1 diabetes mellitus (DM) model was set up in adult male albino rats by single intraperitoneal injection of streptozotocin (65mg/kg, I.P). The third, the fifth, and the seventh groups are non-diabetic groups of rats receiving pentoxifylline (40mg/kg/day, orally), diltiazem (10 mg/kg/day, i.p.), or rosuvastatin (10mg/kg/day, orally), respectively, for eight weeks. The fourth, the sixth, and the eighth groups are diabetic rats receiving pentoxifylline (40 mg/kg per day, orally), diltiazem (10mg/kg per day, i.p.), or rosuvastatin (10mg/kg/day, orally), respectively, for eight weeks. The glomerular filtration rate, serum urea, creatinine, urine albumin, urine volume changes, Na + excretion level, K + excretion level, renal blood flow, renal histopathology, and measurement of antioxidant enzymes activity (GSH, superoxide dismutase) of the different groups were tested compared to control group. Results. At the end of the eight weeks, use of pentoxifylline and rosuvastatin induced significant reduction of serum creatinine, urea, and urine albumin. Also, glomerular filtration rate, renal blood flow, and antioxidant enzymes were significantly improved. There were no significant differences between the two drugs, while diltiazem induced insignificant improvement in the previous parameters. Conclusion. The use of pentoxifylline and rosuvastatin is associated with a reduced risk of diabetic nephropathy by improving oxidative stress. Furthermore, diltiazem insignificantly ameliorates diabetic nephropathy.

INTRODUCTIONDiabetes mellitus (DM) is a major global health problem that causes several micro-and macro-vascular complications. Among these is diabetic nephropathy (DN). DN is the main cause of end-stage renal disease and is associated with a high morbidity and mortality. It develops due to a complex interaction between metabolic and haemodynamic pathophysiological factors, which lead to renal damage. In the earliest stage of DN, patient usually presents with an increase in urinary albumin excretion (microalbuminuria) which progress to macroalbuminuria (more than 300 mg in a 24-hour collection) and later renal insufficiency. 1Among the various mechanisms involved in the pathogenesis of diabetic nephropathy, abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. NO is postulated to play a protective role towards ischemic injuries of vascular tissues including renal vascular endothelium, an action mediated via cyclic guanosine monophosphate (cGMP) which initiates renal vascular smooth muscle relaxation.2 NO plays numerous physiological roles in the kidney, including control of renal and glomerular hemodynamics, dilates both the ABSTRACT Background: Among various mechanisms involved in the pathogenesis of diabetic nephropathy (DN), abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. Tadalafil, a competitive inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 commonly used in the treatment of erectile dysfunction was suggested to play a potential prophylactic role for DN. However, this role has not been fully elucidated. The present study was designed to explore the potential beneficial effect of low-dose tadalafil on the progression of diabetic nephropathy in streptozotocin (STZ) induced diabetic rat model. Methods: After injection of STZ and verifying establishment of diabetes, rats were divided into 4 groups: control, diabetic-control, tadalafil-treated nondiabetic, and tadalafil-treated diabetic groups. Biochemical and hemodynamic parameters affecting the renal function such as blood glucose level, serum level of urea and creatinine, renal blood flow, urine volume, urinary albumin excretion, Na+ and K+ excretion, renal level of nitrite and nitrate, plus renal tissues antioxidant parameters (total antioxidant capacity, superoxide dismutase activity and glutathione content) were detected 8 weeks after administration of tadalafil. Histopathological and electron microscopy examination were performed. Results: Our results demonstrated that tadalafil attenuated the glycemic, renal biochemical, microscopic and ultramicroscopic changes/injuries caused by STZ-induced diabetes. Tadalafil could effectively increase renal blood flow and ameliorate glomerular basement membrane thickening. Conclusions: From the results it can be concluded that tadalafil protects rats against streptozotocin-induced DN possibly, in part, through its effect on renal nitric oxide level and its antioxidant activity.