Renal protective effects and mechanism of losartan in young rats with glomerulosclerosis

Objectives Clinical and experimental studies indicate that angiotensin II (AT II) plays a pathophysiological role in the progression of chronic renal diseases. Angiotensin converting enzyme inhibitor (ACEI) therapy is now widely regarded as a fundamental component of strategies designed to retard the progression of chronic renal diseases. In diabetic patients,ACEI resulted in greater renal protective effects in randomized trials. AT II type-1 (AT1) receptor antagonists (RA),a novel class of renin- angiotensin system inhibitors,inhibit the effects of AT II mediated by AT1 receptors, through which they show protective effects predominantly on glomerulosclerosis. Most of these findings came through the studies in adult animals and humans. However,the renal protective effect of AT1 RA has not,so far,been extensively stu- died in young animals or children and the precise mechanism of this effect remains unclear. The purpose of this study was to observe protective effects of losartan using a model of the focal and segmental glomerulosclerosis in young rats and to find out the mechanism regulating the accumulation of extracellular matrix (ECM). Methods All experiments were performed on 17 male SD rats (one- month- old,weighing 100 g or so) in three groups: control (n = 5),model (n = 6) and losartan-treated (n = 6). Control group were subjected to sham operation and were injected with normal saline after one week via the tail vein. Glomerulosclerosis in young rats was established by means of uninephrectomy and adriamycin (5 mg/kg) administration. After uninephrectomy,losartan- reated group were treated with losartan 5 mg/(kg·d) for 12 weeks. The levels of urinary protein excretion,serum total protein,albumin,serum creatinine,blood urea nitrogen and total cholesterol were measured at regular intervals. The expression of transforming growth factor- β1 (TGF- β1) in the glomeruli was detected by streptavidin/peroxidase staining. The renal pathological changes of the remnant kidney were investigated at the end of experiment. Results Compared to model group losartan showed effect on reducing the proteinuria at 9 and 12 weeks urinary protein excretion (2.41,1.97) mg/24h vs. (17.28,7.39) mg/24h (P 0.01) and (2.96,3.54) mg/24h vs. (14.20,0.55) mg/24h (P 0.01),respectively?. A mild mesangial proliferation at the 12th week after treatment [mesangial expansion rate (3.45,3.36) % vs. (35.40,40.28) %,P 0.05],glomerulosclerosis [sclerosis index (0.25,0.13) vs. (1.86, 2.61),P 0.05] and less expression of TGF- β1 [optical density value (0.143 ± 0.023) vs. (0.221 ± 0.036),P 0.01?] in the injured glomeruli were found in losartan- treated rats. Conclusions These results suggest that losartan show renoprotective effects in reducing proteinuria,mesangial proliferation and glomerular sclerosis in a young rat model with glomerulosclerosis. The lowered expression of TGF- β1 after losartan treatment in the injured glomeruli might be partially responsible for this beneficial effect on accumulation of ECM .