c-Fos-driven transcriptional activation of transforming growth factor β-1: inhibition of high glucose-induced promoter activity by thiazolidinediones☆
Section snippets
Methods
Materials. Troglitazone was kindly provided by Sankyo Pharmaceuticals (Tokyo, Japan). Rosiglitazone was a generous gift of Glaxo SmithKline (Muenchen, Germany). Mouse mesangial cell line SV40 MES [26] was obtained from ATCC (Manassas, USA). Oligonucleotides were synthesized by Life Technologies (Karlsruhe, Germany). Cell culture media, supplements, Ultroser, and fetal calf serum (FCS) were from Gibco (Eggenstein, Germany); Klenow enzyme and poly[d(I–C)] were from Boehringer (Mannheim, Germany);
Effect of TZDs on c-Fos-induced TGF-β1 promoter activation
First we studied the impact of the transcription factor c-Fos on TGF-β1 promoter activity. Transient transfection of SV40 MES, which we used to obtain higher transfection efficiencies and expression levels compared to transfection of porcine mesangial cells, with the c-Fos expression vector resulted in clearly elevated nuclear levels of c-Fos protein (Fig. 1B). In co-transfection experiments the overexpression of c-Fos induced the activity of the TGF-β1 promoter construct −453/+11 (Fig. 1A)
Discussion
We investigated the interaction of TZDs, namely troglitazone and rosiglitazone, with the c-Fos-driven transcriptional activation of the prosclerotic cytokine TGF-β1 in mesangial cells. First, we demonstrated that increases in nuclear c-Fos protein levels are sufficient to induce TGF-β1 promoter activity. Second, we found that treatment with TZDs did not reduce nuclear translocation or transcriptional activity of c-Fos or prevent phorbol ester-stimulated c-Fos expression and activity. Third, we
Acknowledgements
The work was supported by the Deutsche Forschungsgemeinschaft (Schl 239-7) to E.S. We gratefully acknowledge the kind support of Dr. H. Horikoshi (Sankyo Pharmaceuticals) and Dr. Seidel (Glaxo SmithKline) and we thank F. Machicao for critical discussion.
References (42)
- et al.
An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ)
J. Biol. Chem.
(1995) - et al.
Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion
Kidney Int.
(2000) - et al.
The effects of thiazolidinediones on vascular smooth muscle cell activation by angiotensin II
Biochem. Biophys. Res. Commun.
(2000) - et al.
Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells
FEBS Lett.
(1997) - et al.
Troglitazone enhances glucose uptake and inhibits mitogen-activated protein kinase in human aortic smooth muscle cells
Atherosclerosis.
(1998) - et al.
Quantification of glomerular TGF-β1 mRNA in patients with diabetes mellitus
Kidney Int.
(1996) - et al.
Inhibition of oxidation of low density lipoprotein by troglitazone
Atherosclerosis
(1996) - et al.
Troglitazone has a scavenging effect on reactive oxygen species
Biochem. Biophys. Res. Commun.
(1997) - et al.
High glucose elevates c-fos and c-jun transcripts and proteins in mesangial cell cultures
Kidney Int.
(1994) - et al.
DNA binding of activator protein-1 is increased in human mesangial cells cultured in high glucose concentrations
Kidney Int.
(1998)
Glomerular epithelial, mesangial, and endothelial cell lines from transgenic mice factor β1 is mediated by the AP-1 complex
Kidney Int.
Peroxisome proliferator-activated receptor γ ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300
J. Biol. Chem.
Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells
Kidney Int.
Peroxisome proliferator-activated receptor (PPAR)-γ expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-γ activator troglitazone
Am. J. Hypertens.
Repression of glucagon gene transcription by peroxisome proliferator-activated receptor γ through inhibition of Pax6 transcriptional activity
J. Biol. Chem.
Characterization of new oral antidiabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats
Diabetes
Effect of troglitazone in insulin-treated patients with type II diabetes mellitus: Troglitazone and Exogenous Insulin Study Group
N. Engl. J. Med.
Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats
J. Clin. Invest.
Unraveling the mechanism of action of thiazolidinediones
J. Clin. Invest.
Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats
Diabetes
Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia
J. Clin. Invest.
Cited by (29)
Diabetic fibrosis
2021, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :In patients with NASH pioglitazone improved advanced fibrosis [263], through effects attributed to reduced expression of fibrogenic growth factors (such as PDGFs) and attenuated inflammation [264]. In the kidney, glitazones may inhibit fibrosis by attenuating high glucose-induced c-Fos-driven TGFß-1 activation in mesangial cells [265]. Some of the protective actions of RAAS inhibition in diabetic patients may involve anti-fibrotic actions.
Microarray analysis of long noncoding RNA expression patterns in diabetic nephropathy
2017, Journal of Diabetes and its ComplicationsCitation Excerpt :A growing number of studies have elucidated the relationship between the AP-1 TF family and DN. Weigert et al. reported that c-FOS can activate TGF-β (Weigert, Brodbeck, Bierhaus, Häring, & Schleicher, 2003). Another study showed that activated AP-1 family members under high glucose condition in the kidney possibly regulate SphK1 expression, promoting the activation of the SphK1-S1P pathway and mediating the pathological progression of DN (Huang et al., 2014).
Critical role for osteopontin in diabetic nephropathy
2010, Kidney InternationalCitation Excerpt :Our and other observations that PPARγ is expressed in mesangial cells help to explain these findings, although the mechanisms for the TZD effect has been obscure.3 In vitro, PPARγ activation impaired mesangial cell growth; TGF-β, plasminogen-activator inhibitor-1 and vascular endothelial growth factor production; and TGF-β activity.3,19,20 We found that TZD or insulin administration both decreased glomerular OPN expression in db/db mice across all treatment groups, but OPN was reduced to a greater extent by the TZDs, paralleling their effects on albuminuria.
Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-β
2009, American Journal of PathologyCitation Excerpt :Antagonism by PPAR-γ involves blockade of Smad2/3-dependent transcriptional responses without preventing ligand-induced Smad activation and nuclear accumulation (A. Ghosh and J. Varga, unpublished data). Moreover, PPAR-γ suppresses the synthesis and secretion of TGF-β in vitro and in vivo by multiple mechanisms, including induction of PTEN,14,36,49,50 and rosiglitazone treatment reduced the accumulation of TGF-β in the lesional skin. Thus, PPAR-γ ligands exert dual antagonistic effects on TGF-β in the context of fibrogenesis by directly disrupting TGF-β signal transduction, and by suppressing TGF-β production.
Advanced Glycation End Products Increase Collagen-specific Chaperone Protein in Mouse Diabetic Nephropathy
2004, Journal of Biological ChemistryCitation Excerpt :TGF-β regulates the expression of the collagen genes and their transcriptional activities. In particular, the promoter analysis of the collagen genes revealed that TGF-β1 regulates the transcription of collagen genes via several cis-elements of their promoters (13). TGF-β also increases HSP47 gene expression in other cell types (29).
GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49
2022, Frontiers in Pharmacology
- ☆
Abbreviations: AP-1, activating protein-1; DAG, diacylglycerol; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; PPARγ, peroxisome proliferator activator receptor; ROS, reactive oxygen species; TZD, thiazolidinedione; VSMCs, vascular smooth muscle cells.