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Enalapril in subantihypertensive dosage attenuates kidney proliferation and functional recovery in normotensive ablation nephropathy of the rat.
Most studies on the antiproliferative action of angiotensin converting enzyme inhibitors (ACEI) were performed in a rat hypertensive remnant kidney model with 5/6 kidney ablation which raised objections about the antihypertensive effect of ACEI and the influence of other antihypertensive drugs administered to remnant kidney control rats. To prevent these objections, a normotensive 4/6 remnant kidney model was elaborated and a subantihypertensive dosage of enalapril was used to evaluate its antiproliferative action. Subtotally nephrectomized rats (Nx) markedly increased the remnant kidney weight during a 4-week period and this rise was prevented by the treatment with enalapril (NxE) (Nx +297+/-35 mg vs. sham-operated +145+/-32 mg, p<0.001; NxE +154+/-35 mg vs. Nx p<0.001). While collagen concentration in the kidney cortex was not increased in sham-operated rats (Sham) in comparison with the control group (Ctrl) at the beginning of the study, the subsequent increase was significant in the Nx group and enalapril did not attenuate this increase (Sham 148+/-5 mg/100 g w.w. vs. Nx 164+/-2 mg/100 g w.w., p<0.01; NxE 161+/-4 mg/100 g w.w. vs. Sham p<0.05). The tubular protein/DNA ratio increase, which was significant in the Nx group, was inhibited by enalapril (Nx 26.2+/-10.5 vs. NxE 15.3+/-2.6, p<0.05). The protein/DNA ratio was much lower in glomeruli, with no significant changes in either the Nx or NxE groups. Serum urea concentrations were slightly higher in the Nx group than in the sham-operated group, but markedly elevated in the NxE group (Nx 10.71+/-0.76 mmol/l vs. Sham 6.10+/-0.33 mmol/l, p<0.001; NxE 28.9+/-2.6 mmol/l vs. Sham p<0.001). Creatinine concentrations in the Nx group were increased in comparison with the sham-operated group and markedly increased in the NxE group (Nx 63.7+/-3.56 micromol/l vs. Sham 37.2+/-2.84 micromol/l, p<0.001; NxE 107.0+/-5.2 micromol/l vs. Sham p<0.001). The clearance of creatinine was lower in the Nx group than in the sham-operated group and was markedly reduced in the NxE group (Nx 0.89+/-0.06 ml/min.g kidney wt. vs. Sham 1.05+/-0.16 ml/min x g kidney wt., p<0.01; NxE 0.58+/-0.029 ml/min x g kidney wt. vs. Sham, p<0.001). Enalapril improved proteinuria in comparison with the Nx group (NxE 5.6+/-0.6 mg/24 h vs. Nx 16.1+/-3.4 mg/24 h, p<0.05). Thus remnant kidney proliferation is substantial even in normotensive rats. It includes both proliferation and collagen accumulation with partial recovery of kidney weight and function, but is accompanied by enhanced proteinuria. Enalapril attenuates the proliferation and decreases proteinuria but prolongs kidney function recovery.
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