The Effect Of Benazepril Hydrochloride On Insulin-like Growth Factor-1 Expression In Renal And Related Factors In Diabetic Rats

Objective To observe the effect of benazepril hydrochloride on urinary insulin-like growth factor-1 (UIGF-1) level, IGF-1 expression in local renal and renal structure and function, and investigate its possible renoprotective mechanisms in diabetic rats.Method 30 Sprague-Dawley (SD) rats were assigned to normal control (Group NC, n=8) and model group. Streptozotoin (STZ)-induced Diabetic model rats were then treated with (Group DM) or without benazepril (Group DT). Peripheral blood glucose was tested weekly in all groups. At the end of the 4th week, fasting blood glucose (FBG), glycosylated hemoglobin A1c (HbA1c), triglyceride (TG), total cholesterol (TC), urinary insulin-like growth factor-1, urinary albumin and urinary retinol-binding protein were tested. The renal tissues of all rats were obtained after the rats sacrifice to observe the structure changes via light microscope and electron microscope, and kidney/body weight ratio were evaluated. IGF-1mRNA expression in local renal was measured by reverse transcription polymerase chain reaction (RT-PCR) and IGF-1 protein expression by Immunohistochemistry.Results1. The levels of FBG and HbA1C in group DM and group DT were significantly higher than that in group NC (all P<0.01), however, there were no statistical differences between group DM and group DT (all P>0.05).2. TC, TG level increased significantly in group DM and group DT when compared with group NC (all P<0.05). No statistical differences were found between group DM and group DT (all P>0.05).3. UICR, UACR, URCR and kidney mass/body mass increased significantly both in group DM and group DT when compared with that in group NC (all P<0.01). Benazepril hydrochloride significantly reduced UICR, UACR, URCR as well as kidney mass/body mass ratio (all P<0.01). In addition, UICR showed positive correlations with FBG, HbA1c , UACR, URCR and kidney mass/body mass ratio, respectively.4. In gross appearance, the volume of kidneys were larger and the color of kidneys were deeper as well as the cortex were thicker in group DM and group DT than that in group NC. Section of kidney was observed under the high power lens HE staining, no pathological lesion of kidney was found in group NC. Pathological changes were much more obvious in group DM. Glomcrulus cell and renal tubular cell were proliferated, hypertrophied, kytoplasm increased, and karyotin staining was deeper in group DM.All these changes were improved in group DT. Mean glomerular cross-sectional area (MGA) and mean glomerular volume (MGV) were significantly higher in group DM and group DT than that in group NC (all P<0.01). These indexes were decreased in group DT when compared with group DM (all P<0.01).5. There were no changes in the structure and width of glomerular basement membrane (GBM), the fusion of epithelial foot processes (FP) and the area of mesangial region by electron microscopes at the end of the 4th week in group NC. GBM was much thicker and FP were markedly destroyed, even vanished in group DM after 4 weeks. Simultaneously, the ultrastructure of GBM became ambiguous, mesangial cells swelled and extracellular matrix accumulated which caused mesangial region to expand intensively. After the treatment of benazepril hydrochloride, the thickness of GBM decreased markedly when compared with that in group DM. It was clear that the ultrastructure of GBM was relatively regular, and the expansion of the mesangial region was improved.6. IGF-1 protein expression were detected in glomcrulus and nephric tubule in all groups by immunohistochemistry. The IGF-1 protein expression in group DM and group DT was significantly higher than that in group NC (P<0.01), however, benazepril hydrochloride significantly inhibit IGF-1 protein expression (P<0.01).7. The expression of IGF-1mRNA in renal cortex in group DT, which was significantly higher than that in group DM (P<0.01), was much lower than that in group NC(P<0.01) .Conclusion Benazepril hydrochloride has some protective effect on diabetic rat kidney, and this protective effect is independent on the hypoglycemic effect. Part of its mechanism may be related with its inhibition effect on IGF-1 overexpression in local renal and its excretion.