ANGIOTENSIN-II-INDUCED HYPERTROPHY OF CULTURED MURINE PROXIMAL TUBULAR CELLS IS MEDIATED BY ENDOGENOUS TRANSFORMING GROWTH-FACTOR-BETA
ANGIOTENSIN-II-INDUCED HYPERTROPHY OF CULTURED MURINE PROXIMAL TUBULAR CELLS IS MEDIATED BY ENDOGENOUS TRANSFORMING GROWTH-FACTOR-BETA
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DOI：
10.1172/jci116710
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发表时间：
1993-09-01
影响因子：
15.9
通讯作者：
ZIYADEH, FN
中科院分区：
文献类型：
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作者：
WOLF, G;MUELLER, E;ZIYADEH, FN
本课题组的前期研究表明，血管紧张素II（ANG II）在无血清培养液中作为单一因子诱导培养的小鼠近端肾小管细胞系（MCT）细胞肥大。本研究旨在检验这一生长效应是由内源性转化生长因子-β（TGF-β）激活介导的假设。外源性TGF-β（1 ng/ml）模拟10（-8）M ANG II观察到的生长效应（抑制DNA合成和诱导细胞肥大）。中和抗TGF-β抗体减弱ANG II诱导的从头蛋白和总RNA合成以及总蛋白含量的增加。该抗体还消除了ANG II介导的对[H-3]胸苷掺入静止MCT细胞的抑制。对照IgG或不相关的抗体没有影响。使用貂肺上皮细胞进行的TGF-β生物测定显示，用ANG II处理的MCT细胞将活性TGF-β释放到细胞培养上清液中。北方印迹分析和半定量cDNA扩增表明，在ANG II刺激MCT细胞后，TGF-β mRNA的稳态水平增加，但在同基因小鼠系膜细胞系中则没有。我们的数据表明，ANG II诱导的MCT细胞肥大是由内源性TGF-β的合成和激活介导的。有趣的是，推测TGF-β可能在早期肾小管细胞肥大和随后在以肾内ANG II活性增加为特征的几种慢性肾损伤模型中观察到的间质瘢痕形成中起作用。
Previous studies by our group have demonstrated that angiotensin II (ANG II), as a single factor in serum-free medium, induces cellular hypertrophy of a cultured murine proximal tubular cell line (MCT). The present study was performed to test the hypothesis that this growth effect was mediated by activation of endogenous transforming growth factor-beta (TGF-beta). Exogenous TGF-beta, (1 ng/ml) mimicked the growth effects observed with 10(-8) M ANG II (inhibition of DNA synthesis and induction of cellular hypertrophy). A neutralizing anti-TGF-beta antibody attenuated the ANG II-induced increase in de novo protein and total RNA synthesis as well as total protein content. This antibody also abolished the ANG II-mediated inhibition of [H-3]thymidine incorporation into quiescent MCT cells. Control IgG or an unrelated antibody had no effect. A bioassay for TGF-beta using mink lung epithelial cells revealed that MCT cells treated with ANG II released active TGF-beta into the cell culture supernatant. Northern blot analysis and semi-quantitative cDNA amplification demonstrated increases in steady-state levels for TGF-beta, mRNA after ANG II stimulation of MCT cells, but not in a syngeneic murine mesangial cell line. Our data indicate that the ANG II-induced hypertrophy in MCT cells is mediated by synthesis and activation of endogenous TGF-beta. It is intriguing to speculate that TGF-beta may play a role in the early tubular cell hypertrophy and the subsequent interstitial scarring observed in several models of chronic renal injury that are characterized by increased activity of intrarenal ANG II.