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NDT Advance Access published online on July 16, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp339
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1

Holger Hägele1, Ramanjaneyulu Allam1, Rahul D. Pawar1,2 and Hans-Joachim Anders1

1 Department of Nephrology, Medical Policlinic, University of Munich, Munich, Germany 2 Division of Rheumatology, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, Bronx, NY 10461, USA

Correspondence and offprint requests to: Hans-Joachim Anders; E-mail: hjanders{at}med.uni-muenchen.de



  Abstract

Background. The molecular pathomechanisms by which viral infections trigger glomerulonephritis remain elusive. In the glomerulus, glomerular endothelial cells (GEnC) first interact with circulating viral particles; hence, we hypothesized that viral RNA, a known inducer of type I interferons and cytokines in dendritic cells, would also elicit proinflammatory antiviral reponses in GEnC.

Methods. Cultured murine GEnC were stimulated with poly I:C RNA and phenotype changes were assessed. Specific antagonists or s.i.RNA were used to determine the mechanisms of RNA uptake and the functional role of putative RNA receptors.

Results. Poly I:C RNA activated GEnC to produce IL-6, CCL2, CCL5, CXCL10, IFN-{alpha} and IFN-β. This was independent of endosomal acidification or MyD88 but required complex formation with cationic lipids to be taken up into GEnC via clathrin-dependent endocytosis. RIG-1- but not MDA5-specific s.i.RNA prevented GEnC activation. Type I interferon production did not activate GEnC in an autocrine–paracrine manner. Complexed RNA also activated GEnC to express ICAM-1 and increased the albumin permeability of GEnC monolayers.

Conclusions. Complexed dsRNA enters GEnC via clathrin endocytosis and activates GEnC via RIG-1 in the cytosol to produce inflammatory cytokines, chemokines and type I interferons. Furthermore, RNA induces ICAM-1 expression and increases GEnC permeability. All of these mechanisms may contribute to the onset or aggravation of glomerulonephritis associated with RNA virus infections.

Keywords: endothelial cells; glomerulonephritis; inflammation; interferon; viral infection

Received for publication: 24. 3.09
Accepted in revised form: 22. 6.09


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