Angiotensin II induces human TGF-β1 promoter activation:: similarity to hyperglycaemia

被引:96
作者
Weigert, C [1 ]
Brodbeck, K [1 ]
Klopfer, K [1 ]
Häring, HU [1 ]
Schleicher, ED [1 ]
机构
[1] Univ Tubingen, Dept Internal Med, Div Endocrinol Metab & Pathobiochem, D-72076 Tubingen, Germany
关键词
diabetic nephropathy; gene expression; protein kinase C; p38; MAPK; transcription factor AP-1;
D O I
10.1007/s00125-002-0843-4
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims/hypothesis. Activation of the renal renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy. Because previous in vitro studies demonstrated the angiotensin II (ang II)-mediated up-regulation of the prosclerotic transforming growth factor beta1 (TGF) we studied the molecular mechanism of ang II-induced TGF-beta1 gene activation. Methods. Mesangial cells were stimulated with 100 nmol/l ang II with or without inhibitors of protein kinase C (PKC) and p38 MAPK and the TGF-beta1 promoter activity was determined by promoter-reporter assays. The effect of ang II on the binding of nuclear proteins to the regulatory AP-1 site B, previously shown to mediate the high glucose-response of the TGF-beta1 promoter, was studied by electrophoretic mobility shift assays. Results. Ang II enhanced the activity of the TGF-beta1 promoter fragment -453/+11 approximately 1.6-fold. Mutation of each of two AP-1 binding sites or inhibition of the PKC- and p38 MAPK-dependent pathways blocked the ang II-stimulated activity completely. Furthermore, ang II activated the binding of nuclear proteins to the AP-1 box B of the TGF-beta1 promoter. These effects were similar to those previously observed with high glucose. Co-incubation with ang II and high glucose had no additive effect on TGF-1 promoter activity, protein binding to the AP-1 box B or activation of p38 MAPK. Conclusion/interpretation. The findings indicate that ang II and hyperglycaemia stimulate the TGF-beta1 gene activation through the same PKC- and p38 MAPK-dependent pathways by the same regulatory elements of the TGF-beta1 promoter. Our data could also be relevant for e.g. hypertension-induced glomerulosclerosis.
引用
收藏
页码:890 / 898
页数:9
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