Glomerular activin A overexpression is linked to fibrosis in anti-Thy1 glomerulonephritis.
BACKGROUND
Activin A, a member of the transforming growth factor-beta (TGF-beta) superfamily of proteins, shares many biological features with the pro-fibrotic cytokine TGF-beta1, 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-beta1, 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-beta 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.


CONCLUSIONS
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.
Gaedeke
Jens
J
Department of Nephrology, Universitätsklinikum Charité, Berlin, Germany. jens.gaedeke@charite.de
Boehler
Torsten
T
Budde
Klemens
K
Neumayer
Hans-H
HH
Peters
Harm
H
D028341:Activins / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000503:physiopathology*; D007249:Inflammation; D028322:Inhibin-beta Subunits / Q000235:genetics*; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D007375:Interleukin-1; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C422405:activin A; D016222:Fibroblast Growth Factor 2; D028341:Activins; D004656:Enalapril; D028322:Inhibin-beta Subunits