Ding G, Pesek-Diamond I, Diamond J R
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey 17033.
Am J Physiol. 1993 Apr;264(4 Pt 2):F577-84. doi: 10.1152/ajprenal.1993.264.4.F577.
Hypercholesterolemia aggravates experimental progressive glomerular injury. Evidence suggests the infiltrating glomerular macrophage (M phi) is a potential effector mechanism for the noxious effects of hypercholesterolemia. Because transforming growth factor (TGF)-beta 1 is secreted by activated M phi s and also stimulates fibronectin production by glomerular cells, we evaluated the kinetics of gene expression for these moieties in glomeruli isolated from nephrotic rats at 3, 7, 11, and 42 days after the delivery of puromycin aminonucleoside (PA). We also assessed whether cholesterol feeding, which raises the glomerular M phi number, alters the glomerular mRNA levels for TGF-beta 1 and fibronectin. Glomerular mRNA levels for TGF-beta 1 and fibronectin in nephrotic rats exhibited a biphasic temporal pattern, decreasing significantly below control at 3 and 7 days after PA but increasing significantly at 11 and 42 days after PA. The upregulated gene expression for TGF-beta 1 and fibronectin at 11 days after PA temporally corresponded to the phase of mesangial M phi infiltration in this model. Cholesterol feeding to both normal and nephrotic rats significantly increased glomerular TGF-beta 1 and fibronectin mRNA levels at 11 days after PA. Immunohistochemical labeling for M phi s and intracellular TGF-beta 1 demonstrated both mesangial and cortical interstitial localization with the TGF-beta1-positive cells possessing M phi nuclear morphology. These findings identify a novel interaction between hypercholesterolemia, augmented glomerular M phi accumulation, and upregulated glomerular TGF-beta 1 and fibronectin gene expression. These perturbations within the acutely injured glomerulus constitute an early pathobiological determinant for the later development of mesangial matrix expansion and glomerulosclerosis.
高胆固醇血症会加重实验性进行性肾小球损伤。有证据表明，浸润性肾小球巨噬细胞（M phi）是高胆固醇血症有害作用的一种潜在效应机制。由于转化生长因子（TGF）-β1由活化的M phi分泌，并且还刺激肾小球细胞产生纤连蛋白，我们评估了在给予嘌呤霉素氨基核苷（PA）后3、7、11和42天从肾病大鼠分离的肾小球中这些部分的基因表达动力学。我们还评估了增加肾小球M phi数量的胆固醇喂养是否会改变TGF-β1和纤连蛋白的肾小球mRNA水平。肾病大鼠中TGF-β1和纤连蛋白的肾小球mRNA水平呈现双相时间模式，在PA后3天和7天显著低于对照水平，但在PA后11天和42天显著升高。PA后11天TGF-β1和纤连蛋白基因表达上调在时间上与该模型中系膜M phi浸润阶段相对应。对正常和肾病大鼠进行胆固醇喂养在PA后11天显著增加了肾小球TGF-β1和纤连蛋白mRNA水平。对M phi和细胞内TGF-β1进行免疫组织化学标记显示，系膜和皮质间质均有定位，TGF-β1阳性细胞具有M phi核形态。这些发现确定了高胆固醇血症、肾小球M phi积累增加以及肾小球TGF-β1和纤连蛋白基因表达上调之间的一种新的相互作用。急性损伤肾小球内的这些紊乱构成了系膜基质扩张和肾小球硬化后期发展的早期病理生物学决定因素。
