caa a22 4500 445882484 CHVBK 20180317145548.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10157-010-0351-7 doi (NATIONALLICENCE)springer-10.1007/s10157-010-0351-7 Glucocorticoid enhances hypoxia- and/or transforming growth factor-β-induced plasminogen activator inhibitor-1 production in human proximal renal tubular cells [Elektronische Daten] [Hideki Kimura, Xuan Li, Kunio Torii, Toshiharu Okada, Kazuko Kamiyama, Daisuke Mikami, Kenji Kasuno, Naoki Takahashi, Haruyoshi Yoshida] Background: Glucocorticoid (GC) treatment reportedly exaggerates renal fibrosis in progressive kidney diseases during which hypoxia occurs as an unavoidable consequence in renal tubular cells. Two major fibrotic factors, hypoxia and transforming growth factor-β (TGF-β), upregulate the production of plasminogen activator inhibitor-1 (PAI-1), a fibrosis enhancer. Most recently, we reported that GC increases PAI-1 production in human proximal tubular epithelial cells (HPTEC). However, the detailed interactions that occur between these PAI-1 inducers in HPTEC remain to be clarified. Methods: Confluent HPTECs were treated with GC and/or TGF-β for 24h under normoxia or hypoxia. The mRNA and protein amounts of PAI-1 and GC receptor (GR) were determined by TaqMan quantitative PCR and immunoassays, respectively. GC and hypoxia response element (GRE and HRE) activities were measured by transient transfection of GRE- and HRE-luciferase expression vector. Results: Hypoxia had no influence on dexamethasone (DXA)-enhanced GRE activity, as DXA had no influence on hypoxia-enhanced HRE activity. Hypoxia induced PAI-1 expression. TGF-β increased basal and hypoxia-stimulated PAI-1 production. Hydrocortisone (HC) and DXA increased hypoxia- or TGF-β-stimulated production of PAI-1 mRNA and protein. Moreover, DXA enhanced hypoxia plus TGF-β-stimulated PAI-1 production. The PAI-1-increasing effect of HC under hypoxia was abolished completely by RU-486, a specific inhibitor of the GR, and largely by PP2, a specific inhibitor of the Src family of protein tyrosine kinases. Conclusion: Glucocorticoid induces hypoxia- and hypoxia plus TGF-β-stimulated PAI-1 production via the GR and tyrosine kinase pathways. These actions of GC may partially explain the renal fibrotic changes seen in progressive inflammatory kidney diseases during GC treatment. Japanese Society of Nephrology, 2010 Glucocorticoid nationallicence Human proximal renal tubular cells nationallicence Hypoxia nationallicence PAI-1 nationallicence TGF-β nationallicence Kimura Hideki Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Li Xuan Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Torii Kunio Department of Clinical Laboratory, University of Fukui Hospital, Fukui, Japan aut Okada Toshiharu Department of Clinical Laboratory, University of Fukui Hospital, Fukui, Japan aut Kamiyama Kazuko Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Mikami Daisuke Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Kasuno Kenji Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Takahashi Naoki Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Yoshida Haruyoshi Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut Clinical and Experimental Nephrology Springer Japan 15/1(2011-02-01), 34-40 1342-1751 15:1<34 2011 15 10157 https://doi.org/10.1007/s10157-010-0351-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10157-010-0351-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kimura Hideki Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 700 1- Li Xuan Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 700 1- Torii Kunio Department of Clinical Laboratory, University of Fukui Hospital, Fukui, Japan aut NATIONALLICENCE 700 1- Okada Toshiharu Department of Clinical Laboratory, University of Fukui Hospital, Fukui, Japan aut NATIONALLICENCE 700 1- Kamiyama Kazuko Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 700 1- Mikami Daisuke Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 700 1- Kasuno Kenji Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 700 1- Takahashi Naoki Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 700 1- Yoshida Haruyoshi Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, 910-1193, Fukui, Japan aut NATIONALLICENCE 773 0- Clinical and Experimental Nephrology Springer Japan 15/1(2011-02-01), 34-40 1342-1751 15:1<34 2011 15 10157 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer