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J. Biol. Chem., Vol. 278, Issue 7, 5091-5098, February 14, 2003

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Steroid Responsiveness of Renal Epithelial Cells
DISSOCIATION OF TRANSREPRESSION AND TRANSACTIVATION^*

Simone de Haij, Ian M. Adcock^§, Astrid C. Bakker, Sam J. P. Gobin^¶, Mohamed R. Daha, and Cees van Kooten

From the Departments of  Nephrology and ^¶ Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands and the ^§ Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London SW3 6LY, United Kingdom

Glucocorticoids modulate cellular and inflammatory responses via stimulation or inhibition of gene transcription. Inhibition of cytokine gene expression is mediated via repression of transcription factors, including NF-B. Previously we have shown that cytokine production by renal epithelial cells is insensitive to the inhibitory action of dexamethasone. In this study we demonstrate that dexamethasone is unable to inhibit NF-B activation in the renal epithelial cell line HK-2, as measured by IB- degradation and DNA binding activity. Transfection of an NF-B-inducible reporter gene demonstrated that non-stimulated HK-2 cells contain a high level of constitutively active NF-B compared with the steroid-sensitive airway epithelial cell line A549, which was not blocked by dexamethasone. Expression and nuclear translocation of the glucocorticoid receptor (GR) was comparable in both cell types. In HK-2 cells, dexamethasone stimulated expression of two glucocorticoid-responsive genes, ₂-adrenoreceptors and angiotensinogen. The capacity of GR to transactivate the native angiotensinogen glucocorticoid-responsive element (GRE) using chromatin-IP was not impaired. Moreover, dexamethasone activation of a GRE-driven reporter construct appeared to be equally effective, although less sensitive compared with A549 cells. In conclusion, we provide evidence that glucocorticoids are unable to repress the activity of NF-B in renal epithelial cells in the presence of an intact stimulatory pathway.

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