Failure of antioxidant therapy to attenuate interstitial disease in rats with reversible nephrotic syndrome.
The present two studies were designed to determine whether oxidized LDL contributes to the tubulointerstitial changes seen in rats during the acute phase of acute puromycin aminonucleoside nephrosis (PAN). In the single-dose study, rats were given one injection of puromycin aminonucleoside (PA; 15 mg/100 g body wt) and killed 1, 2, or 3 wk thereafter. The four animal groups were saline controls, PAN controls, PAN plus probucol, and PAN plus lovastatin. This study showed that the addition of probucol significantly reduced the mean levels of serum cholesterol and renal lipid-peroxidation products, an effect not seen with lovastatin therapy. Compared with saline controls, PAN controls had a significant increase in total kidney collagen (7.9 +/- 1.2 versus 5.9 +/- 0.6 mg/kidney at 3 wk). Neither probucol nor lovastatin therapy attenuated the interstitial inflammation or fibrosis. In the multidose study, 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 controls, PAN plus probucol, and PAN plus vitamin E. Hepatic lipid-peroxidation products were significantly lower in the probucol-treated, but not in the vitamin E-treated, PAN groups when compared with the PAN controls. Neither probucol nor vitamin E prevented the increase in total kidney 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, versus 5.4 +/- 0.5 mg/kidney for the saline controls). Renal cortical mRNA levels for matrix-encoding genes and protease inhibitors were similar in the three nephrotic groups. Transforming growth factor-beta1 mRNA levels were highly variable within each group and not significantly different at day 35, but showed a significant positive correlation with the degree of albuminuria (r = 0.70). The present results demonstrate that the treatment of acutely nephrotic rats with antioxidant therapy did not attenuate interstitial inflammation or fibrosis. We speculate that other factors, possibly a consequence of proteinuria itself, are the predominant pathogenetic mediators of the tubulointerstitial damage in acute nephrotic syndrome.
Drukker
A
A
Shaare Zedek Medical Centre, Hebrew University Medical School, Jerusalem, Israel.
Eddy
A A
AA
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000032:analysis / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000032:analysis; D005355:Fibrosis / Q000473:pathology; D007668:Kidney / Q000033:anatomy & histology / Q000737:chemistry / Q000187:drug effects; D008054:Lipid Peroxides / Q000032:analysis; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008856:Microscopy, Fluorescence; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D009929:Organ Size; D011341:Probucol / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria; D011692:Puromycin Aminonucleoside / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000032:analysis; D017211:Treatment Failure; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D000975:Antioxidants; D005353:Fibronectins; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D016212:Transforming Growth Factor beta; D014810:Vitamin E; D011692:Puromycin Aminonucleoside; D003094:Collagen; D002784:Cholesterol; D008148:Lovastatin; D011341:Probucol