Renal protective effects of blocking the intrarenal renin-angiotensin system

Abstract

It has been well demonstrated that angiotensin converting enzyme inhibitors (ACEIs) can retard the progression of renal failure and kidney sclerosis in patients and animal models with glomerular diseases. The aim of this study was to observe the influences of ACEI on intrarenal Ang II and TGFβ1 local formation and their relation to renal protective effects. Experimental glomerulosclerosis with nephrotic syndrome was induced in unilateral nephrectomized rats with repeated injections of adriamycin. Rats were randomly divided into three groups: 1) a sham-operated control group (n = 8); 2) an NS group treated with ACEI (benazepril 4 mg/kg/d) (n = 10), and 3) an NS group not treated (n = 10). After 8 wk, serum, urine and renal tissue mere collected for study. ACE activity and Ang II concentration in renal tissue were measured by colorimetry and radioimmunoassay, respectively. Immunohistochemistry staining was employed for transforming growth factor-β1 (TGFβ1) and extracellular matrix (ECM) examination. TGFβ1 mRNA was assessed by in situ hybridization. Compared with those of non-treated nephropathy rats, ACE activity (13.39 ± 5.02 vs. 49.13 ± 12.92 U/ml, p < 0.01) and Ang II (402.61 ± 80.22 vs. 751.63 ± 137.45 pg/mg/pr p < 0.01) in renal tissue were significantly inhibited in the rats treated with ACEI. At the same time, proteinuria was significantly reduced (155.06 ± 103.56 vs. 421.11 ± 148.45 mg/24 h, p < 0.01) and renal function improved (Scr 76.3 ± 33.1 vs. 107.1 ± 71.0, p < 0.05), concomitant with a reduction in the glomerular sclerosis index (30.6 ± 19.5 vs. 120.3 ± 61.9, p < 0.01) and a reduction in ECM accumulation such as Col IV, III, LN and FN (29.2 ± 9.8 vs. 76.8 ± 12.4; 29.5 ± 12.4 vs. 85.9 ± 11.5; 26.0 ± 5.1 vs. 69.6 ± 1.73; 32.4 ± 12.4 vs. 70.5 ± 13.5; p < 0.01 in all cases). In the ACEI treated group, these histologic benefits coincided with a reduced expression of TGFβ1 in both tubular cells and sclerosed glomeruli in protein as well as mRNA level. These findings provide further evidence that ACEI (benazepril) can prevent the progression of renal damage in both the function and morphologic changes which associated with a down-regulation of intrarenal Ang II level through the relative inhibition of renal ACE activity. The blocking of the intrarenal renin angiotensin system (RAS) might contribute to the inhibition of TGFβ1 local formation and the TGF(β)1-mediated ECM accumulation that are related to the renal protective effects of ACEI.