FAILURE OF ANTIOXIDANT THERAPY TO ATTENUATE INTERSTITIAL DISEASE IN RATS WITH REVERSIBLE NEPHROTIC SYNDROME

The present two studies were designed to determine whether oxidized LD L contributes to the tubulointerstitial changes seen in rats during th e acute phase of acute puromycin aminonucleoside nephrosis (PAN). In t he single-dose study, rats were given one injection of puromycin amino nucleoside (PA; 15 mg/100 g body wt) and killed 1, 2, or 3 wk thereaft er. The four animal groups were saline controls, PAN controls, PAN plu s probucol, and PAN plus lovastatin. This study showed that the additi on of probucol significantly reduced the mean levels of serum choleste rol and renal lipid-peroxidation products, an effect not seen with lov astatin therapy. Compared with saline controls, PAN controls had a sig nificant increase in total kidney collagen (7.9 +/- 1.2 versus 5.9 +/- 0.6 mg/kidney at 3 wk). Neither probucol nor lovastatin therapy atten uated the interstitial inflammation or fibrosis. In the multidose stud y, rats were given the same initial PA dose and were uninephrectomized on day 12. They were killed on day 35 after two smaller PA doses were given on days 16 and 23. Animal groups were saline controls, PAN cont rols, PAN plus probucol, and PAN plus vitamin E. Hepatic lipid-peroxid ation products were significantly lower in the probucol-treated, but n ot in the vitamin E-treated, PAN soups when compared with the PAN cont rols. Neither probucol nor vitamin E prevented the increase in total k idney collagen that was observed in the PAN control group (7.4 +/- 0.7 , 10.1 +/- 2.6, and 9.3 +/- 1.8 mg of collagen/kidney, respectively, v ersus 5.4 +/- 0.5 mg/kidney for the saline controls). Renal cortical m RNA levels for matrix-encoding genes and protease inhibitors were simi lar in the three nephrotic groups. Transforming growth factor-beta 1 m RNA levels were highly variable within each group and not significantl y differ ent at day 35, but showed a significant positive correlation with the degree of albuminuria (r = 0.70). The present results demonst rate that the treatment of acutely nephrotic rats with antioxidant the rapy did not attenuate interstitial inflammation or fibrosis. We specu late that other factors, possibly a consequence of proteinuria itself, are the predominant pathogenetic mediators of the tubulointerstitial damage in acute nephrotic syndrome.