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

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 β1 (TGF) we studied the molecular mechanism of ang II-induced TGF-β1 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-β1 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-β1 promoter, was studied by electrophoretic mobility shift assays. Results. Ang II enhanced the activity of the TGF-β1 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-β1 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-β1 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-β1 gene activation through the same PKC-and p38 MAPK-dependent pathways by the same regulatory elements of the TGF-β1 promoter. Our data could also be relevant for e.g. hypertension-induced glomerulosclerosis. [Diabetologia (2002) 45:890-898]

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

“…However, mesangial cell hypertrophy induced by endothelin-1 is independent of p38 MAPK signalling [32]. High glucose and angiotensin II also promote TGF-β1 gene activation in mesangial cells by p38 MAPK signalling [33]. This in turn contributes to fibrosis [7,8].…”

Drug Treatment of Hypertension: Focus on Vascular Health

“…Angiotensin II acts through two receptors -AT1 and AT2, with AT1 activation playing a major role in the production of ECM proteins and vascular fibrosis 2,[95][96][97][98] . Whilst the precise mechanisms involved in angiotensin II related vascular fibrosis remain to be fully defined, increased activity of TGF-β-1, galectin-3, p38 MAPK and MMPs/TIMPs may all contribute.…”

High glucose-induced Matrilin-2 expression in mouse mesangial cells was mediated by transforming growth factor beta 1 (TGF-β1)

“…The mesangial ECM is the main cause of declining renal function in DN provides structural support for the glomerular capillary convolute, connecting with the extraglomerular mesangium at the vascular pole and dysregulation of cell-matrix signaling plays an important role in DN [2]. It was found that hyperglycemia induced TGF-expression in experimental and human diabetes [20,21]. Previous findings have demonstrated that high glucose stimulates TGF-β1 very early through its receptor [22,23].…”