Glucocorticoids protect renal mesangial cells from apoptosis by increasing cellular sphingosine-1-phosphate

Förster, Ankathrin; Emmler, Tanja; Schwalm, Stephanie; Ebadi, Mahsa; Heringdorf, Dagmar Meyer Zu; Nieuwenhuis, Barbara; Kleuser, Burkhardt; Huwiler, Andrea; Pfeilschifter, Josef (2010). Glucocorticoids protect renal mesangial cells from apoptosis by increasing cellular sphingosine-1-phosphate. Kidney international, 77(10), pp. 870-9. New York, N.Y.: Nature Publishing Group 10.1038/ki.2010.62

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Neutral ceramidase (NCDase) and sphingosine kinases (SphKs) are key enzymes regulating cellular sphingosine-1-phosphate (S1P) levels. In this study we found that stress factor-induced apoptosis of rat renal mesangial cells was significantly reduced by dexamethasone treatment. Concomitantly, dexamethasone increased cellular S1P levels, suggesting an activation of sphingolipid-metabolizing enzymes. The cell-protective effect of glucocorticoids was reversed by a SphK inhibitor, was completely absent in SphK1-deficient cells, and was associated with upregulated mRNA and protein expression of NCDase and SphK1. Additionally, in vivo experiments in mice showed that dexamethasone also upregulated SphK1 mRNA and activity, and NCDase protein expression in the kidney. Fragments (2285, 1724, and 1126 bp) of the rat NCDase promoter linked to a luciferase reporter were transfected into rat kidney fibroblasts and mesangial cells. There was enhanced NCDase promoter activity upon glucocorticoids treatment that was abolished by the glucocorticoid receptor antagonist RU-486. Single and double mutations of the two putative glucocorticoid response element sites within the promoter reduced the dexamethasone effect, suggesting that both glucocorticoid response elements are functionally active and required for induction. Our study shows that glucocorticoids exert a protective effect on stress-induced mesangial cell apoptosis in vitro and in vivo by upregulating NCDase and SphK1 expression and activity, resulting in enhanced levels of the protective lipid second messenger S1P.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Schwalm, Stephanie and Huwiler, Andrea

ISSN:

0085-2538

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:09

Last Modified:

04 May 2014 23:04

Publisher DOI:

10.1038/ki.2010.62

PubMed ID:

20375982

Web of Science ID:

000277169800007

URI:

https://boris.unibe.ch/id/eprint/870 (FactScience: 201117)

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