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NDT Advance Access published online on January 18, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn756
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Dexamethasone enhances basal and TNF-{alpha}-stimulated production of PAI-1 via the glucocorticoid receptor regardless of 11β-hydroxysteroid dehydrogenase 2 status in human proximal renal tubular cells

Hideki Kimura1, Xuan Li1, Kunio Torii2, Toshiharu Okada2, Kazuko Kamiyama1, Daisuke Mikami1, Naoki Takahashi1 and Haruyoshi Yoshida1

1 Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui 2 Department of Clinical Laboratory, University of Fukui Hospital, Fukui, Japan

Correspondence and offprint requests to: Hideki Kimura, Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, Fukui, 910-1193, Japan. Tel: +81-776-61-3111 (ext. 3361); Fax: +81-776-61-8120; E-mail: hkimura{at}u-fukui.ac.jp



  Abstract

Background. Long-term treatment with glucocorticoids (GCs) reportedly exaggerates renal fibrosis in chronic progressive inflammatory kidney disease. GCs induce the gene expression of plasminogen activator inhibitor-1 (PAI-1), a fibrosis enhancer in non-renal cells. Tumour necrosis factor-alpha (TNF-{alpha}) reduces the gene expression of 11β-hydroxysteroid dehydrogenase (HSD) 2, an inactivator of GCs, and may enhance GC activity. However, the individual and collective effects of adrenal steroids, TNF-{alpha} and HSD2 status on PAI-1 production are unknown in human proximal renal tubular epithelial cells (HPTECs).

Methods. Confluent HPTECs were treated with adrenal steroids (10 nM to 10 µM) or TNF-{alpha} (10 ng/ml) for up to 48 h. The mRNA amounts of the target genes were determined by TaqMan quantitative PCR, and the PAI-1 protein amounts were measured by an immunoassay.

Results. Dexamethasone (DXA) maximally increased the amounts of PAI-1 mRNA and protein at 100 nM. Aldosterone (Ald) increased PAI-1 expression dose dependently, but the effect was over 100-fold weaker than that of DXA. The PAI-1-increasing effects of DXA and Ald were abolished completely by U-486, a specific inhibitor of the glucocorticoid receptor (GR) but not by spironolactone, a specific inhibitor of the mineralocorticoid receptor. The effect of DXA was also blocked partially by AG1478 and herbimycin A, tyrosine kinase inhibitors. DXA further increased TNF-{alpha}-stimulated PAI-1 expression via the GR. Although TNF-{alpha} treatment caused an 80% reduction in the gene expression of HSD2, an inactivator of GCs, HSD2 inhibition did not enhance DXA-induced PAI-1 production.

Conclusions. DXA induces basal and TNF-{alpha}-stimulated PAI-1 expression via the GR pathway, regardless of HSD2 status in HPTECs. Excess GCs may serve as a pro-fibrotic factor in chronic inflammatory kidney diseases.

Keywords: dexamethasone; human proximal tubular cells; PAI-1; TNF-{alpha}

Received for publication: 27. 9.08
Accepted in revised form: 16.12.08


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