Effects of enalapril and paricalcitol treatment on diabetic nephropathy and renal expressions of TNF-α, p53, caspase-3 and Bcl-2 in STZ-induced diabetic rats.

Abstract

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.