Nephrol Dial Transplant Vol. 20 No. 2 © ERA–EDTA 2005; all rights reserved
Original Article
Glomerular activin A overexpression is linked to fibrosis in anti-Thy1 glomerulonephritis
Department of Nephrology, Universitätsklinikum Charité, Berlin, Germany
Correspondence and offprint requests to: Jens Gaedeke, MD, Med. Klinik m.S. Nephrologie, Charité, Campus Mitte, Schumannstr. 20–21, D-10117 Berlin, Germany. Email: jens.gaedeke{at}charite.de
Background. Activin A, a member of the transforming growth factor-ß (TGF-ß) superfamily of proteins, shares many biological features with the pro-fibrotic cytokine TGF-ß1, which is primarily responsible for the accumulation of extracellular matrix proteins in renal disease. This study was designed to identify regulators of activin A production in glomerular mesangial cells and test if activin A acts as a pro-fibrotic cytokine in mesangial cells.
Methods. The effect of inflammatory cytokines on activin A production and the effect of exogenous activin A on mediators of fibrosis were analysed in cultured rat mesangial cells. Expression of activin A and of established mediators of fibrosis was analysed in a rat model of glomerular fibrosis (anti-Thy1 glomerulonephritis).
Results. In cultured mesangial cells, interleukin-1 and basic fibroblast growth factor, both mediators of glomerular inflammatory injury, dose-dependently increased activin A expression. Incubation with activin A significantly stimulated TGF-ß1, PAI-1 and connective tissue growth factor RNA expression and increased production of extracellular matrix proteins in mesangial cells. In rats with anti-Thy1 glomerulonephritis, expression of glomerular activin A mRNA and protein paralled the expression of TGF-ß and other indices of fibrosis, showing little change from normal on day 1, a marked, 70-fold increase of activin protein production on day 6, and a subsequent decrease at day 12. Antifibrotic therapy with the angiotensin-converting enzyme inhibitor enalapril significantly reduced glomerular activin A production.
Conclusion. Taken together, the results of this study link overexpression of activin A to glomerular matrix protein expansion in vivo and in vitro, suggesting that activin A acts as pro-fibrotic cytokine in renal disease.
Keywords: activin A; anti-Thy1 glomerulonephritis; fibrosis; glomerular disease; rat; TGF-ß
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