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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/F407    most recent 00093.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Giehl, K. Articles by Goppelt-Struebe, M. PubMed PubMed Citation Articles by Giehl, K. Articles by Goppelt-Struebe, M.

The small GTPase Rac-1 is a regulator of mesangial cell morphology and thrombospondin-1 expression

¹Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm; and ²Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany

Submitted 23 February 2007 ; accepted in final form 27 November 2007

Thrombospondin-1 (TSP-1), which is synthesized by mesangial cells, is known for its anti-angiogenic activity and its ability to activate latent TGF-β. TSP-1 is upregulated in renal diseases associated with tissue remodeling. Therefore, we hypothesized that the expression of TSP-1 might be modulated by changes in cell morphology involving proteins of the Rho family. Spreading of mesangial cells after detachment and reseeding was characterized by the formation of lamellipodia and focal adhesions, pointing toward a Rac-1-mediated rearrangement of actin structures. Clustering of focal adhesion proteins was also observed in a model system of nocodazole-induced disruption of microtubules. These morphological alterations were impeded by pharmacological inhibition of Src family kinases, of the small GTPase Rac-1, or by downregulation of Rac-1 by siRNA. Upon cell spreading, TSP-1 was upregulated in the absence and much more prominently in the presence of serum, but also after nocodazole treatment. TSP-1 upregulation was controlled by activation of Src family kinases, ERK 1/2 and Rac-1, whereas activation of RhoA-ROCK signaling was not linked to TSP-1 induction. We thus provide evidence that TSP-1 expression is induced by common signaling pathways, which are activated by morphological alterations of renal mesangial cells or by soluble factors as contained in serum, and these pathways include Src family kinases, ERK 1/2 and Rac-1. Our data suggest that tissue remodeling activates gene expression of pathophysiologically relevant proteins such as TSP-1.

cytoskeleton; Src kinases; Rho proteins