Background: Increased permeability of glomerular capillary wall in adriamycin nephropathy may be mediated by increased generation of free radicals and possibly also by the non-enzymatic production of isoprostanes induced by oxidative stress. ACE inhibitors may reduce proteinuria, possibly due to the decrease of intraglomerular pressure and increased permselectivity of the glomerular capillary wall. These effects may be partly mediated by the inhibition of the degradation of kinins. It is not clear if newly available angiotensin II antagonists have the same antiproteinuric and renoprotective effects.
Methods and results: We compared the effect of an ACE inhibitor (enalapril, 0.4 mg/kg bw i.p. daily for 3 weeks) and angiotensin II antagonist (losartan, 2 mg/kg bw in the same way) on experimental nephrotic syndrome induced in rats by the administration of adriamycin (5 mg/kg bw i.v. in a single dose). To elucidate the potential differences between these two drugs we also measured total malondialdehyde in blood and urinary excretion some eicosanoids and their metabolites (TxB2, 6-keto-PGF1alfa, bicyclo-PGE2 and 8-isoprostane). Proteinuria increased in adriamycin treated rats after 3 weeks from 0.18 +/- 0.01 to 0.44 +/- 0.14 g/mmol creat, p < 0.01. This increase was not prevented by losartan (increase from 0.18 +/- 0.12 to 0.50 +/- 0.11 g/mmol creat, p < 0.05), but tended to be partly blunted by enalapril (increase from 0.20 +/- 0.10 to only 0.32 +/- 0.08 g/mmol creat, p < 0.05). Similarly there was no increase of serum cholesterol, only in enalapril treated rats. On the other hand, both losartan (1.27 +/- 0.13 vs. 1.91 +/- 0.30 mumol/l, p < 0.05) and enalapril (0.93 +/- 0.06 mumol/l, p < 0.001) prevented adriamycin induced increase of total MDA in serum, but urinary excretion of 8-isoprostane was increased in nephrotic rats treated by losartan compared to controls. Enalapril induced increase of urinary excretion of bicyclo-PGE2 (4.32 +/- 0.62 vs. 1.66 +/- 0.81 ng/mmol creat, p < 0.001) was possibly mediated by kinins. There was no significant difference in the urinary excretion of other eicosanoids between different groups, but proteinuria correlated positively with urinary excretion of 8-isoprostane (p < 0.01). Proteinuric rats had also significantly higher urinary excretion of 8-isoprostane than non-proteinuric rats (44.8 +/- 7.1 vs. 26.7 +/- 3.4 ng/mmol. creat, p < 0.05).
Conclusions: Our data suggest that proteinuria in adriamycin nephropathy may mainly depend on free radical generation and the formation of 8-isoprostane. Haemodynamic parameters (glomerular pressure) do not seem to be so important. The mild antiproteinuric effect of enalapril may suggest a contributory role of the inhibition of kinin degradation in this model of nephrotic syndrome.