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 1 surgical N; eight littermates were pretreated with losartan (L) only for 6 weeks prior to 1 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 1 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.
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Acknowledgements. We thank Tom Groppoli and Frida Maiers for the electron microscopic imaging and Patricia L. Erickson for assistance with manuscript preparation. This work was partially supported by an academic research grant from Merck, USA. Dr H.W.P. was supported by a research grant from Seoul National University College of Medicine.
- angiotensin receptor blockade
- focal segmental glomerulosclerosis
- interstitial fibrosis
- renal ablation