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Crosstalk between peroxisome proliferator-activated receptor-γ and mineralcorticoid receptor in TNF-α activated renal tubular cell

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Abstract

Introduction

In our previous study, we observed the crosstalk between peroxisome proliferator-activated receptor-γ (PPAR-γ) and angiotensin II in activated renal tubular cells. The present study is aimed to further explore the crosstalk between PPAR-γ and mineralocorticoid receptor (MR) in tumor necrosis factor (TNF)-α activated renal tubular cells.

Methods

Human proximal renal tubular epithelial cells HK-2 were cultured with the pre-treatment of PPAR-γ agonist, pioglitazone (5 μM), MR antagonist, eplerenone (5 μM), or their combined treatment, followed by activation with TNF-α (20 ng/ml). In the parallel experiment, PPAR-γ inhibitor GW9662 (25 µM) was used to study the independence of PPAR-γ. Gene expression and protein synthesis of intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), MR and PPAR-γ were measured by RT-PCR, ELISA and Western blot, respectively; nuclear factor κB (NF-κB) nuclear translocation activity in the nucleus was examined by EMSA assay.

Results

TNF-α effectively activated HK-2 cells by up-regulating gene expression and protein synthesis of ICAM-1, IL-6 and MR and down-regulating PPAR-γ in a dose-dependent manner. TNF-α also significantly induced NF-κB nuclear translocation in HK-2 cells. Dual treatment of pioglitazone and eplerenone demonstrated synergistic effect on reducing ICAM-1 and IL-6 expression and alleviating NF-κB activation when compared with their monotherapies in TNF-α activated renal tubular cells. PPAR-γ antagonist, GW9662, significantly attenuated protective effect on ICAM-1, IL-6 and PPAR-γ expression by pioglitazone, eplerenone and their combined treatment.

Conclusions

Our data suggest that pioglitazone, in a PPAR-γ-dependent manner, trans-represses MR signaling by suppressing NF-κB activation. MR antagonist also restored PPAR-γ expression. Dual treatment of pioglitazone and eplerenone present better efficacy in attenuating excessive inflammatory response in activated renal tubular cells under stimulation of TNF-α than single treatment.

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Acknowledgments

This research is supported by National Natural Science Foundation of China (Grant Number 30900684/C140405). The results in this paper have been presented in the poster form in World Congress of Nephrology 2013 (May 31 to June 4, Hong Kong).

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Authors and Affiliations

  1. Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China

    Jing Xiao, Weijun Chen, Yijun Lu, Xiaoli Zhang, Chensheng Fu, Zhenwen Yan, Zhenxing Zhang & Zhibin Ye

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  1. Jing Xiao
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Correspondence to Zhibin Ye.

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Xiao, J., Chen, W., Lu, Y. et al. Crosstalk between peroxisome proliferator-activated receptor-γ and mineralcorticoid receptor in TNF-α activated renal tubular cell. Inflamm. Res. 64, 603–614 (2015). https://doi.org/10.1007/s00011-015-0838-5

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  • DOI: https://doi.org/10.1007/s00011-015-0838-5

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