| IntroductionInsulin resistance (IR) is an independent risk factor to the occurrence of renal damage and renal failure, and the damage of renal structure and function has appeaeed at its hyperinsulinemia stage. Vascular endothelial growth factor (VEGF) can promote endothelial cell proliferation and migration, to increase vascular permeability, to change extracellular matrix after binding its receptors, which is the one of main reasons for leading to microalbuminuria of kidney disease, playing a key role in kidney damage by IR. Telmisartan, a new angiotensin receptor blocker (ARB), can reduce blood pressure as well as insulin resistance.ObjectiveTo observe the expressions of vascular endothelial growth factor (VEGF) and its receptor flt-1, flk-1 in the kidney and the protective effect of telmisartan on renal injury at normal blood glucose stage in insulin-resistant rats.MethodsAll rats were randomly divided into three groups:the control group (C), fed by basic chow; the group of Insulin resistance (IR), fed by high-fat diet; and the intervening group by telmisartan (T), fed by high-fat and telmisartan diet. High-fat diet for 6 weeks was used to establish the rat model of insulin resistance with normal blood sugar and the intervention of telmisartan, and the euglycemic-hyperinsulinemic clamp technique (EHCT) was used to evaluate the model. Lipid levels were determined by the automatic biochemistry analysor; serum free fatty acids (FFA) was determined by the colorimetry; plasma insulin by the radioimmunoassay; urinary microalbumin was determined by the immunoturbidimetry; the change in the organizational structure of the kidney was observed by electron microscope; the expression of renal cortical VEGF and flk-1 mRNA was detected by semi-quantitative RT-PCR; the expression of VEGF, flt-1, flk-1 in glomerulars was detected by immunohistochemistry; correlation analysis of the data.Results1. Compared with C group, fasting plasma insulin(FINS), serum free fatty acid(FFA), triglyceride(TG) and total cholesterol(TC) level decrease significantly in IR group rats (12.21±2.02 VS 29.21±9.89, P<0.001; 0.28±0.24 VS 0.56±0.30, P<0.01; 0.13±0.09 VS 0.54±0.21, P<0.001; 0.66±0.31 VS 1.53±0.27, P<0.001), but the average glucose infusion rate during 60min-120min(GIR60-120) and insulin sensitivity index(ISI) decrease significantly in IR group rats (7.03±0.99 VS 0.37±0.28, P<0.001;-3.92±0.14 VS-4.89±0.41, P<0.001). plasma FINS has positively correlation with BINS, FFA, TG, TC and negative correlation with GIR60-120 (P<0.001), but ISI has positively correlation with GIR60-120 (P<0.01) and negative correlation with BINS, FFA, TG, TC (P<0.001,P<0.01,P<0.01,P<0.001). Compared with IR group, through telmisartan interventing, plasma FINS, TG and TC level decrease significantly (29.21±9.89 VS 17.50±2.88, P<0.05; 0.54±0.21 VS 0.40±0.22, P<0.001; 1.53±0.27 VS 1.11±0.92, P<0.001), but GIR60-120 and ISI increase significantly in T group rats(0.37±0.28 VS 0.49±0.31, P<0.01;-4.89±0.41 VS-4.24±0.27, P<0.01).2. Compared with C group, the glomerular basement membrane (GBM) of IR group rats thickens significantly (0.18±0.03 VS 0.35±0.09, P<0.001) and has uneven thickness; foot process swelling and lacking or integrating, barriers structure damaged. Lipid droplets are found in renal tubular epithelial cells. Glomerular area(GA), glomerular volume(GV) and microalbuminuria(MAU) increase significantly in IR group rats (4.13±0.83 VS 4.89±0.62, P<0.01; 7.77±1.56 VS 9.20±1.16, P<0.01; 0.39±0.17 VS 1.79±0.67, P<0.05). Compared with IR group, through telmisartan interventing, the thickening becomes no significant in the glomerular basement membrane of T group rats (0.35±0.09 VS 0.25±0.07, P<0.05), and foot process is neatly arranged. GA, GV, MAU are significantly lower than these of IR group rats (4.89±0.62 VS 4.42±0.33, P<0.05; 9.20±1.16 VS 8.32±0.62, P<0.05; 1.79±0.67 VS 0.62±0.24, P<0.05)3. Compared with C group, the VEGF and flk-1 mRNA expressions significantly increase in the renal cortex of IR group rats (0.67±0.01 VS 0.98±0.14, P<0.001; 0.38±0.06 VS 0.58±0.02, P<0.001); The VEGF and flt-1, flk-1 protein expressions increase significantly in the glomerulars of IR group rats (2.25±0.82 VS 4.06±0.36, P<0.001; 1.69±0.40 VS 4.13±0.28, P<0.001; 1.46±0.26 VS 3.79±0.37, P<0.001), and positively correlate with MAU, GA, GV. Compared with IR group, through telmisartan interventing, the VEGF and flk-1 mRNA expressions decrease significantly in renal cortical of T group rats (0.98±0.14 VS 0.75±0.01, P<0.001; 0.58±0.02 VS 0.49±0.05, P<0.01), and the VEGF and flt-1, flk-1 protein expressions significantly decrease in the glomerulars of T group rats (4.06±0.36 VS 2.81±0.39, P<0.001; 4.13±0.28 VS 3.18±0.58, P<0.01; 3.79±0.37 VS 2.82±0.52, P<0.01).Conclusions1. At normal blood glucose stage, kidney damage has appeared in IR rats, which has GBM thickening, foot process swelling and lacking or integrating, glomerular hypertrophy and microalbuminuria.2. VEGF is involved in the mechanism of kidney damage in IR rats. 3. Telmisartan can relieve the state of insulin resistance, to inhibit the high expression of VEGF and its receptor flt-1, flk-1 in the kidney, to improve structural and fuctional changes of the kidney, and to reduce the occurrence of glomerular hypertrophy and microalbuminuria.
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