Isaka Y, Tsujie M, Ando Y, Nakamura H, Kaneda Y, Imai E, Hori M
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Kidney Int. 2000 Nov;58(5):1885-92. doi: 10.1111/j.1523-1755.2000.00360.x.
Interstitial expression of transforming growth factor-beta1 (TGF-beta1) is important in tubulointerstitial fibrosis, a common process in most progressive renal diseases. However, no effective therapy for progressive interstitial fibrosis is known. Recently, we developed an artificial viral envelope (AVE)-type hemagglutinating virus of Japan (HVJ) liposome-mediated retrograde ureteral gene transfer method, which allowed us to introduce the genetic material selectively into renal interstitial fibroblasts.
We introduced antisense or scrambled oligodeoxynucleotides (ODNs) for TGF-beta 1 into interstitial fibroblasts in rats with unilateral ureteral obstruction, a model of interstitial fibrosis, to block interstitial fibrosis by retrograde ureteral injection of AVE-type HVJ liposomes.
TGF-beta 1 and type I collagen mRNA increased markedly in the interstitium of untreated obstructed kidneys, and those were not affected by scrambled ODN transfection. Northern analysis and in situ hybridization revealed that the levels of TGF-beta 1 and type I collagen mRNA were dramatically decreased in antisense ODN-transfected obstructed kidneys. Consequently, the interstitial fibrotic area of the obstructed kidneys treated with antisense ODN was significantly less than that of the obstructed kidneys untreated or treated with scrambled ODN.
The introduction of TGF-beta 1 antisense ODN into interstitial fibroblasts may be a potential therapeutic maneuver for interstitial fibrosis.
转化生长因子-β1（TGF-β1）的间质表达在肾小管间质纤维化中起重要作用，这是大多数进行性肾脏疾病中的常见过程。然而，目前尚无针对进行性间质纤维化的有效治疗方法。最近，我们开发了一种人工病毒包膜（AVE）型日本血凝病毒（HVJ）脂质体介导的逆行输尿管基因转移方法，该方法使我们能够将遗传物质选择性地导入肾间质成纤维细胞。
我们将针对TGF-β1的反义或乱序寡脱氧核苷酸（ODN）导入单侧输尿管梗阻大鼠的间质成纤维细胞中，这是一种间质纤维化模型，通过逆行输尿管注射AVE型HVJ脂质体来阻断间质纤维化。
在未处理的梗阻肾脏间质中，TGF-β1和I型胶原mRNA显著增加，而乱序ODN转染对其无影响。Northern分析和原位杂交显示，反义ODN转染的梗阻肾脏中TGF-β1和I型胶原mRNA水平显著降低。因此，用反义ODN处理的梗阻肾脏的间质纤维化面积明显小于未处理或用乱序ODN处理的梗阻肾脏。
将TGF-β1反义ODN导入间质成纤维细胞可能是治疗间质纤维化的一种潜在策略。
