Production of inflammatory mediators by renal epithelial cells is insensitive to glucocorticoids

Haij, Simone de; Woltman, Andrea M.; Bakker, Astrid C.; Daha, Mohamed R.; Kooten, Cees van

doi:10.1038/sj.bjp.0704866

Cited by 38 publications

(32 citation statements)

References 43 publications

(43 reference statements)

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“…GR knockdown experiments did not prevent the effect of aldosterone on NF-Binduced transcripts. Moreover, in contrast with a previous report from de Haij et al 36 that NF-B-controlled cytokine production is insensitive to dexamethasone in renal epithelial cells, we observed a strong reduction of LPS-or aldosterone-induced cytokine mRNA accumulation in CD cells. Because inhibition of the NF-B pathway by glucocorticoids relies on GRdependent transrepression or transactivation mechanisms, 37 it is very unlikely that GR mediates aldosterone-dependent NF-B activation.…”

Section: Discussioncontrasting

confidence: 99%

Aldosterone Activates NF-κB in the Collecting Duct

Leroy

Seigneux²,

Agassiz³

et al. 2009

Journal of the American Society of Nephrology

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Besides its classical effects on salt homeostasis in renal epithelial cells, aldosterone promotes inflammation and fibrosis and modulates cell proliferation. The proinflammatory transcription factor NF-B has been implicated in cell proliferation, apoptosis, and regulation of transepithelial sodium transport. The effect of aldosterone on the NF-B pathway in principal cells of the cortical collecting duct, a major physiologic target of aldosterone, is unknown. Here, in both cultured cells and freshly isolated rat cortical collecting duct, aldosterone activated the canonical NF-B signaling pathway, leading to increased expression of several NF-B-targeted genes (IB␣, plasminogen activator inhibitor 1, monocyte chemoattractant protein 1, IL-1␤, and IL-6). Small interfering RNA-mediated knockdown of the serum and glucocorticoid-inducible kinase SGK1, a gene induced early in the response to aldosterone, but not pharmacologic inhibition of extracellular signal-regulated kinase and p38 kinase, attenuated aldosterone-induced NF-B activation. Pharmacologic antagonism or knockdown of the mineralocorticoid receptor prevented aldosterone-induced NF-B activity. In addition, activation of the glucocorticoid receptor inhibited the transactivation of NF-B by aldosterone. In agreement with these in vitro findings, spironolactone prevented NF-B-induced transcriptional activation observed in cortical collecting ducts of salt-restricted rats. In summary, aldosterone activates the canonical NF-B pathway in principal cells of the cortical collecting duct by activating the mineralocorticoid receptor and by inducing SGK1.

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Section: Discussioncontrasting

confidence: 99%

Aldosterone Activates NF-κB in the Collecting Duct

Leroy

Seigneux²,

Agassiz³

et al. 2009

Journal of the American Society of Nephrology

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“…Whole cell extracts were prepared as described previously (17). Cell extracts (10 g) were separated with SDS-PAGE, transferred to membranes, and blocked in Tris-buffered saline/0.1% Tween-20 containing 5% nonfat dry milk.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Therefore, it is important to identify the signaling pathways involved in the regulation of cytokine gene expression by TEC, which might be a target for therapeutic intervention. We have already demonstrated an important role for NF-B (16,17). In this study, we have investigated the contribution of MAP kinase pathways to cytokine production by the renal epithelial cells on activation with TNF-␣, IL-1, IL-17, or CD40L.…”

mentioning

confidence: 97%

NF-κB Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase

Haij¹,

Bakker²,

Geest³

et al. 2005

Journal of the American Society of Nephrology

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“…Glucocorticoids are potent suppressors of the immune system and are known to inhibit cytokine production by a variety of cell types (5-7). However, we have shown previously that cytokine and chemokine production by activated renal tubular epithelial cells is insensitive to the inhibitory action of dexamethasone (8). The present study was undertaken to investigate the mechanism of steroid action in renal epithelial cells.…”

Section: Discussionmentioning

confidence: 94%

“…Although glucocorticoids are known to have a profound inhibitory effect on cytokine production by a variety of cell types (5-7), we have previously shown that production of inflammatory mediators by renal tubular epithelial cells is insensitive to the inhibitory action of glucocorticoids (8). Inhibition of cytokine production by glucocorticoids has been attributed to transrepression of NF-B, a pro-inflammatory transcription factor that regulates the expression of many inflammatory mediators, including IL-6 and IL-8 (9,10).…”

mentioning

confidence: 99%

Steroid Responsiveness of Renal Epithelial Cells

Haij¹,

Adcock²,

Bakker³

et al. 2003

Journal of Biological Chemistry

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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 I B-␣ 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 glucocorticoidresponsive 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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Production of inflammatory mediators by renal epithelial cells is insensitive to glucocorticoids

Cited by 38 publications

References 43 publications

Aldosterone Activates NF-κB in the Collecting Duct

Aldosterone Activates NF-κB in the Collecting Duct

NF-κB Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase

Steroid Responsiveness of Renal Epithelial Cells

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