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NDT Advance Access originally published online on March 26, 2008
Nephrology Dialysis Transplantation 2008 23(8):2496-2503; doi:10.1093/ndt/gfn139
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


A natural PPAR-{gamma} agonist, 15-deoxy-delta 12,14-prostaglandin J2, may act as an enhancer of PAI-1 in human proximal renal tubular cells under hypoxic and inflammatory conditions

Hideki Kimura1, Xuan Li1, Kunio Torii1, Toshiharu Okada1, Naoki Takahashi1, Hiroshi Fujii2, Shunji Ishihara3 and Haruyoshi Yoshida1

1 Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 2 Department of Biochemistry, School of Medicine, Niigata University, Niigata 3 Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Shimane, 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, kimura.hideki{at}maroon.plala.or.jp



  Abstract

Background. Hypoxia and inflammation, an unavoidable milieu for renal tubular cells during the development of renal fibrosis, reportedly up-regulate production of plasminogen activator inhibitor-1 (PAI-1), a promoter of tissue fibrosis. Peroxisome proliferator-activated receptor (PPAR)-{gamma} agonists may modulate renal fibrosis progression via their anti-inflammatory effects in a PPAR-{gamma}-dependent or -independent manner. However, no information is known about the effects of PPAR-{gamma} agonists on PAI-1 expression in human proximal renal tubular cells (HPTECs) under hypoxia and/or inflammation.

Methods. Confluent HPTECs were exposed to normoxia (18% O2), hypoxia (1% O2) and/or TNF-{alpha} at 10 ng/mL for up to 48 h. The cells were incubated with two PPAR-{gamma} ago- nists, 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) and pioglitazone. Precise amounts of PAI-1 mRNA and protein were measured by TaqMan quantitative PCR and immunoassay, respectively. PPAR response element (PPRE) activity induced by 15d-PGJ2 was measured by transfection with PPRE-luciferase construct.

Results. Basal PAI-1 was significantly increased, in a dose-dependent manner, by 15d-PGJ2. It also enhanced hypoxia-, TNF-{alpha}- and hypoxia plus TNF-{alpha}-stimulated PAI-1 expression at the mRNA and protein levels. Pioglitazone had no influence on PAI-1 protein production. Although 15d-PGJ2 enhanced PPRE activity significantly in the HPTECs expressing PPAR-{gamma}, a specific inhibitor for PPAR-{gamma}, GW9662, did not diminish 15d-PGJ2-induced PAI-1 expression. In contrast, a non-selective tyrosine kinase (TK) inhibitor, genisteine or a MEK1 (MAPK kinase) inhibitor, PD98059, inhibited 15d-PGJ2-induced PAI-1 production completely.

Conclusions. The endogenous PPAR-{gamma} agonist, 15d-PGJ2, increased PAI-1 expression independently of PPAR-{gamma} via the activation of TK or MAP kinase in HPTECs and may act as an enhancer of PAI-1 production in the kidney under hypoxic and inflammatory conditions.

Keywords: 15d-PGJ2; human proximal tubular cells; hypoxia; PAI-1; PPAR-{gamma}

Received for publication: 1. 7.07
Accepted in revised form: 20. 2.08


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