Eddy A A
Hospital for Sick Children, Toronto, Ontario, Canada.
Kidney Int. 1998 May;53(5):1182-9. doi: 10.1046/j.1523-1755.1998.00889.x.
Uninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TCF-beta 1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase-type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-beta 1 mRNA levels (to 150%), although TGF-beta 1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.
饮食诱导的高胆固醇血症的单侧肾切除大鼠在8至12周后会出现间质炎症和纤维化。纤维化与脂质过氧化产物在肾小管间质内的积累有关，同时转化生长因子β-1（TGF-β1）、一些基质蛋白和金属蛋白酶组织抑制剂（TIMP-1）的肾mRNA水平升高。然而，已发现尿激酶型纤溶酶原激活剂（uPA）的mRNA水平降低。本研究的目的是确定抗氧化治疗是否能减轻高胆固醇血症大鼠的间质纤维化，并确定抗氧化治疗诱导的肾基因表达模式的变化。对三组单侧肾切除大鼠进行了研究，它们分别在喂食标准大鼠饲料、致动脉粥样硬化饮食（标准饲料加4%胆固醇/1%胆酸）或补充高剂量抗氧化剂普罗布考和维生素E的致动脉粥样硬化饮食12周后接受观察。与喂食标准饲料的大鼠相比，喂食致动脉粥样硬化饮食的大鼠出现了高胆固醇血症，总肾胶原蛋白增加了56%。相比之下，用抗氧化剂治疗的高胆固醇血症大鼠的肾脂质过氧化产物水平正常，肾胶原蛋白含量也正常。相反，两个高胆固醇血症组之间的尿白蛋白排泄率或间质巨噬细胞数量没有显著差异。与未治疗的高胆固醇血症组相比，抗氧化治疗使前胶原III（降至未治疗水平的60%）、胶原IV（60%）和TIMP-1（20%）的肾mRNA水平显著降低，而uPA水平显著升高（升至210%）。矛盾的是，抗氧化治疗与肾TGF-β1 mRNA水平显著升高（升至150%）有关，尽管TGF-β1蛋白表达主要从间质细胞转移到肾小管上皮细胞。本研究结果证明了抗氧化治疗在预防单肾高胆固醇血症大鼠肾间质纤维化方面的有效性。基于mRNA水平的肾基因表达变化，基质蛋白合成受损以及金属蛋白酶和uPA/纤溶酶的肾内活性增加可能在纤维化的减轻中起作用。
