Akagi Y, Isaka Y, Arai M, Kaneko T, Takenaka M, Moriyama T, Kaneda Y, Ando A, Orita Y, Kamada T, Ueda N, Imai E
First Department of Medicine, Osaka University School of Medicine, Japan.
Kidney Int. 1996 Jul;50(1):148-55. doi: 10.1038/ki.1996.297.
Overproduction of transforming growth factor-beta 1 (TGF-beta 1) has been implicated in the pathogenesis of fibrotic diseases. TGF-beta 1 plays a crucial role in the accumulation of extracellular matrix (ECM) in human and experimental glomerular diseases. However, it remains unclear whether inhibition of TGF-beta 1 overproduction would suppress TGF-beta 1-induced ECM accumulation. To inhibit the overproduction of TGF-beta 1 in experimental glomerulonephritis induced by anti-Thy 1.1 antibody, we introduced antisense oligodeoxynucleotides (ODN) for TGF-beta 1 into the nephritic kidney by the HVJ-liposome-mediated gene transfer method. Sense, scrambled or reverse ODN were also introduced as controls. Transfected ODN accumulated mainly in the nuclei of mesangial cells in the glomeruli of transfected kidneys. In the antisense ODN-transfected rats, a marked decrease in expression of TGF-beta 1 mRNA was confirmed by Northern analysis. Consequently, the expression of TGF-beta 1 protein in the glomerulus was markedly reduced in the antisense ODN-transfected kidney with a comparable effect in preventing glomerular ECM expansion in experimental glomerulonephritis. In contrast, sense, scrambled and reverse ODNs failed to suppress TGF-beta 1 expression and ECM accumulation. Thus, these results suggested that inhibition of TGF-beta 1 overproduction could suppress progression to glomerulosclerosis.
转化生长因子β1（TGF-β1）的过度产生与纤维化疾病的发病机制有关。TGF-β1在人类和实验性肾小球疾病的细胞外基质（ECM）积累中起关键作用。然而，抑制TGF-β1的过度产生是否会抑制TGF-β1诱导的ECM积累仍不清楚。为了抑制抗Thy 1.1抗体诱导的实验性肾小球肾炎中TGF-β1的过度产生，我们通过HVJ-脂质体介导的基因转移方法将TGF-β1的反义寡脱氧核苷酸（ODN）导入患肾。作为对照，还导入了正义、乱序或反向ODN。转染的ODN主要积聚在转染肾脏肾小球系膜细胞的细胞核中。在反义ODN转染的大鼠中，通过Northern分析证实TGF-β1 mRNA的表达明显降低。因此，在反义ODN转染的肾脏中，肾小球中TGF-β1蛋白的表达明显降低，在预防实验性肾小球肾炎中肾小球ECM扩张方面具有类似的效果。相比之下，正义、乱序和反向ODN未能抑制TGF-β1的表达和ECM积累。因此，这些结果表明抑制TGF-β1的过度产生可以抑制肾小球硬化的进展。
