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.