This study aimed to assess the renopreventive effect of enalapril and/or paricalcitol on streptozotocin (STZ) diabetes-induced nephropathy and to elucidate their mechanisms of action through investigation of the effects on renal oxidative stress, antioxidant defense system and expressions of TNF-α, p53, caspase-3, and Bcl-2. Diabetes mellitus was induced in fasting male Wistar rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) dissolved in citrate buffer (pH 4.5). Ten days after STZ injection, the diabetic rats were treated with enalapril (25 mg/l of drinking water) and/or paricalcitol (8 μg/kg b.w. per os) dissolved in 5% DMSO daily for 4 weeks. The obtained data revealed that the treatment of diabetic Wistar rats with enalapril and/or paricalcitol led to significant decreases in the elevated serum urea, uric acid, creatinine, sodium and potassium levels; thereby reflecting the improvement of the impaired kidney function. The deteriorated kidney lipid peroxidation, GSH content and GST and catalase activities in diabetic rats were significantly ameliorated as a result of treatment with enalapril and/or paricalcitol. The elevated fasting and post-prandial serum glucose levels and the lowered serum insulin and C-peptide levels were also improved. The treatment with enalapril and paricalcitol in combination was the most potent in decreasing the elevated serum glucose levels. Moreover, the treatment of diabetic rats successfully prevented the diabetes-induced histopathological deleterious changes of kidney and islets of Langerhans of pancreas. In association, the immunohistochemically detected pro-inflammatory cytokine, TNF-α, and apoptotic mediators, p53 and caspase-3, were remarkably decreased in kidney of diabetic rats as a result of treatment while the expression of anti-apoptotic protein Bcl-2 was increased. Based on these findings, it can be concluded that enalapril and paricalcitol alone or in combination can prevent STZ diabetes-induced nephropathy through amelioration of the glycemic state and antioxidant defense system together with the suppression of oxidative stress, inflammation and apoptosis. However, the treatment of diabetic rats with enalapril and paricalcitol in combination has no further significant improvement effects on renal function and damage when compared with enalapril or paclitaxel treated diabetic groups.

21This study aimed to assess the renopreventive effect of the angiotensin converting 22 enzyme inhibitor (ACEI), enalapril, and/or vitamin D receptor (VDR) activator, paricalcitol, 23 on streptozotocin (STZ) diabetes-induced nephropathy and to elucidate the mechanisms of 24 action through investigation of the effects on renal oxidative stress, antioxidant defense 25 system and expressions of TNF-α, P53, caspase-3, and Bcl-2. Diabetes mellitus was induced 26 in fasting male Wistar rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) 27 dissolved in citrate buffer pH 4.5. Ten days after STZ injection, the diabetic rats were treated 28 with enalapril (25 mg/l of drinking water) and/or paricalcitol (8 µg/kg b.w. per os) dissolved 29 in 5% DMSO daily for 4 weeks. The obtained data revealed that the treatment of diabetic 30 Wistar rats with enalapril and/or paricalcitol led to a significant decrease in the elevated 31 serum urea, uric acid, creatinine and sodium, potassium levels; thereby reflecting 32 improvement of the impaired kidney function. The deteriorated kidney lipid peroxidation, 33 GSH content and GST and catalase activities in diabetic rats were significantly ameliorated 34 as a result of treatment with enalapril and/or paricalcitol. The elevated fasting and post-35 prandial serum glucose levels and the lowered serum insulin and C-peptide levels were also 36improved. Moreover, the treatment of diabetic rats successfully prevented the diabetes-37 induced histopathological deleterious changes of kidney and islets of Langerhans of pancreas. 38In association, the immunohistochemically detected pro-inflammatory cytokine TNF-α and 39 apoptotic mediators P53 and caspase-3 were remarkably decreased in kidney of diabetic rats 40 as a result of treatment, while the expression of anti-apoptotic protein Bcl-2 was increased. 41Based on these findings, it can be concluded that enalapril and paricalcitol can prevent STZ 42 diabetes-induced nephropathy though amelioration of the glycemic state and antioxidant 43 defense system together with the suppression of oxidative stress, inflammation and apoptosis.44