Drukker A, Eddy A A
Shaare Zedek Medical Centre, Hebrew University Medical School, Jerusalem, Israel.
J Am Soc Nephrol. 1998 Feb;9(2):243-51. doi: 10.1681/ASN.V92243.
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.
目前的两项研究旨在确定氧化型低密度脂蛋白是否会导致急性嘌呤霉素氨基核苷肾病（PAN）急性期大鼠出现肾小管间质改变。在单剂量研究中，给大鼠注射一次嘌呤霉素氨基核苷（PA；15mg/100g体重），并在1、2或3周后处死。四个动物组分别为生理盐水对照组、PAN对照组、PAN加普罗布考组和PAN加洛伐他汀组。该研究表明，添加普罗布考可显著降低血清胆固醇和肾脂质过氧化产物的平均水平，而洛伐他汀治疗未观察到这种效果。与生理盐水对照组相比，PAN对照组的总肾胶原蛋白显著增加（3周时分别为7.9±1.2mg/肾和5.9±0.6mg/肾）。普罗布考和洛伐他汀治疗均未减轻间质炎症或纤维化。在多剂量研究中，大鼠给予相同的初始PA剂量，并在第12天进行单侧肾切除。在第16天和第23天给予两次较小剂量的PA后，于第35天处死。动物组分别为生理盐水对照组、PAN对照组、PAN加普罗布考组和PAN加维生素E组。与PAN对照组相比，普罗布考治疗的PAN组肝脂质过氧化产物显著降低，但维生素E治疗的PAN组未降低。普罗布考和维生素E均未阻止PAN对照组中观察到的总肾胶原蛋白增加（分别为7.4±0.7、10.1±2.6和9.3±1.8mg胶原蛋白/肾，而生理盐水对照组为5.4±0.5mg/肾）。三个肾病组肾皮质中基质编码基因和蛋白酶抑制剂的mRNA水平相似。转化生长因子-β1 mRNA水平在每组中高度可变，在第35天时无显著差异，但与蛋白尿程度呈显著正相关（r = 0.70）。目前的结果表明，用抗氧化疗法治疗急性肾病大鼠并未减轻间质炎症或纤维化。我们推测，其他因素，可能是蛋白尿本身的结果，是急性肾病综合征肾小管间质损伤的主要致病介质。
