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Published ahead of print on July 2, 2009
J Am Soc Nephrol 20: 1963-1974, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008060653
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BASIC RESEARCH

Nitric Oxide Inhibits Glomerular TGF-β Signaling via SMOC-1

Ellen Dreieicher*, Karl-Friedrich Beck*, Sandra Lazaroski*, Meike Boosen*, Wasiliki Tsalastra-Greul*, Martina Beck*, Ingrid Fleming{dagger}, Liliana Schaefer* and Josef Pfeilschifter*

*Pharmazentrum Frankfurt/ZAFES,
{dagger}Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Correspondence: Dr. Karl-Friedrich Beck, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D 60590 Frankfurt am Main, Germany. Phone: +49-069-6301-6953; Fax: +49-069-6301-7942; E-mail: k.f.beck{at}em.uni-frankfurt.de

Received for publication June 27, 2008. Accepted for publication April 29, 2009.

Cytokines and nitric oxide (NO) stimulate rat mesangial cells to synthesize and secrete inflammatory mediators. To understand better the signaling pathways that contribute to this response, we exposed rat mesangial cells to the prototypic inflammatory cytokine IL-1β and analyzed the changes in the pattern of gene expression. IL-1β downregulated the gene encoding the matricellular glycoprotein secreted modular calcium-binding protein 1 (SMOC-1) in mesangial cells. Inflammatory cytokines attenuated SMOC-1 mRNA and protein expression through endogenous production of NO, which activated the soluble guanylyl cyclase. Silencing SMOC-1 expression with small interfering RNA decreased the formation of TGF-β, reduced SMAD binding to DNA, and decreased mRNA expression of genes regulated by TGF-β. In a rat model of anti–Thy-1 glomerulonephritis, glomerular SMOC-1 mRNA and protein decreased and inducible NO synthase expression increased simultaneously. Treatment of nephritic rats with the inducible NO synthase–specific inhibitor L-N6-(1-iminoethyl)-lysine prevented SMOC-1 downregulation. In summary, these data suggest that NO attenuates SMOC-1 expression in acute glomerular inflammation, thereby limiting TGF-β–mediated profibrotic signaling.






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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673