| Dexamethasone enhances basal and TNF-alpha-stimulated production of PAI-1 via the glucocorticoid receptor regardless of 11beta-hydroxysteroid dehydrogenase 2 status in human proximal renal tubular cells. | |
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MedLine Citation:
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PMID: 19153071 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 11beta-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 microM) 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. |
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Authors:
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Hideki Kimura; Xuan Li; Kunio Torii; Toshiharu Okada; Kazuko Kamiyama; Daisuke Mikami; Naoki Takahashi; Haruyoshi Yoshida |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-01-18 |
Journal Detail:
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Title: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Volume: 24 ISSN: 1460-2385 ISO Abbreviation: Nephrol. Dial. Transplant. Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-05-21 Completed Date: 2009-08-25 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8706402 Medline TA: Nephrol Dial Transplant Country: England |
Other Details:
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Languages: eng Pagination: 1759-65 Citation Subset: IM |
Affiliation:
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Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. hkimura@u-fukui.ac.jp |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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11-beta-Hydroxysteroid Dehydrogenase Type 2
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antagonists & inhibitors,
genetics,
metabolism* Aldosterone / pharmacology Cells, Cultured Dexamethasone / adverse effects, pharmacology* Fibrosis Humans Kidney Tubules, Proximal / drug effects*, metabolism*, pathology Plasminogen Activator Inhibitor 1 / biosynthesis*, genetics Protein-Tyrosine Kinases / metabolism RNA, Messenger / genetics, metabolism Receptors, Glucocorticoid / antagonists & inhibitors, drug effects*, metabolism* Receptors, Mineralocorticoid / metabolism Tumor Necrosis Factor-alpha / pharmacology* Tyrphostins / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Plasminogen Activator Inhibitor 1; 0/RNA, Messenger; 0/Receptors, Glucocorticoid; 0/Receptors, Mineralocorticoid; 0/SERPINE1 protein, human; 0/Tumor Necrosis Factor-alpha; 0/Tyrphostins; 170449-18-0/tyrphostin AG 1478; 50-02-2/Dexamethasone; 52-39-1/Aldosterone; EC 1.1.1.146/11-beta-Hydroxysteroid Dehydrogenase Type 2; EC 2.7.10.1/Protein-Tyrosine Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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