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Diabetologia. 2002 Jun;45(6):890-8. Epub 2002 May 17.

Angiotensin II induces human TGF-beta 1 promoter activation: similarity to hyperglycaemia.

Author information

1
Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Tübingen, Germany.

Abstract

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 beta 1 (TGF) we studied the molecular mechanism of ang II-induced TGF-beta 1 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-beta 1 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-beta 1 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-beta 1 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-beta 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-beta 1 gene activation through the same PKC- and p38 MAPK-dependent pathways by the same regulatory elements of the TGF-beta 1 promoter. Our data could also be relevant for e.g. hypertension-induced glomerulosclerosis.

PMID:
12107734
DOI:
10.1007/s00125-002-0843-4
[Indexed for MEDLINE]

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