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

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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-α) 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-α 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-α (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-α-stimulated PAI-1 expression via the GR. Although TNF-α 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-α-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.

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