Angiotensin II receptor blocker pretreatment of rats undergoing sudden renal ablation

BACKGROUND: Subtotal nephrectomy (N) in rats results in progressive hypertension, proteinuria and renal lesions. Renin-angiotensin system blockade initiated at N prevents these changes; treatments failing to reduce hypertension and proteinuria do not. METHODS: Ten Munich-Wistar rats underwent 1½ surgical N; eight littermates were pretreated with losartan (L) only for 6 weeks prior to 1½ N (N + L). Pretreated (n = 8; C + L) and untreated controls (C; n = 8) had sham operations. RESULTS: Over 6 months, N and N + L rats developed ∼80% increase in glomerular filtration rate per nephron over C and C + L, P < 0.001). Hypertension (intra-arterial mean blood pressure 116 ± 6.8 mmHg in N rats versus 102 ± 3.2 in C, 104 ± 8.4 in C + L, and 104 ± 8.4 in N + L rats, P < 0.001 for all) and proteinuria (120 ± 20 mg/day in N versus 39 ± 10 in C, 34 ± 8 in C + L and 35 ± 8 in N + L, P < 0.001 for all) developed only in N. Focal segmental glomerulosclerosis (FSGS) (%) at 6 months was 20 ± 8 in N and 17.5 ± 8 in N + L (ns) and <1 in C and C + L (P < 0.001 versus N and N + L). Interstitial fractional volume (Vv), 4.0 ± 1.7% in C and 4.4 ± 1.6% in C + L (ns), was similarly increased to 7.5 ± 2.5% in N and 9.0 ± 3.9% in N+L (P < 0.04 versus C and C + L). Atrophic tubule Vv was increased by >300% in N and N + L over C and C + L (P < 0.02 for all). Glomerular volume doubled in N and N + L (P < 0.001). Podocyte foot process effacement was greater in N and NL than in C or C + L (P ≤ 0.02 for all). Thus, L given for 6 weeks prior to 1½ N prevented hypertension and proteinuria over the subsequent 6 months without reducing glomerular hypertrophy, hyperfiltration or interstitial, tubular or FSGS lesions or foot process effacement. CONCLUSIONS: These studies dissociated systemic hypertension and proteinuria from the renal lesions in this model. Durable effects of losartan on blood pressure and proteinuria likely represent epigenetic processes.