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NDT Advance Access originally published online on July 2, 2008
Nephrology Dialysis Transplantation 2008 23(11):3427-3436; doi:10.1093/ndt/gfn319
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


PDE-5 inhibition impedes TSP-1 expression, TGF-β activation and matrix accumulation in experimental glomerulonephritis

Bernd Hohenstein, Christoph Daniel, Sandra Wittmann and Christian Hugo

Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany

Correspondence and offprint requests to: Bernd Hohenstein, Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Loschgestrasse 8, 91054 Erlangen, Germany. Tel: +49-9131-8532122; Fax: +49-9131-8539209; E-mail: bernd.hohenstein{at}rzmail.uni-erlangen.de



  Abstract

Background. Matrix expansion and mesangial proliferation are hallmarks of mesangial proliferative glomerulonephritis. Specific inhibition of PDE-5, an enzyme catalyzing the intracellular degradation of cyclic GMP, can be achieved by the inhibitor vardenafil. In this study, we investigated the effects of PDE-5 inhibition in the anti-Thy1 model in the rat in vivo.

Methods. After disease induction, rats received 10 mg/kg bw vardenafil twice a day via gavage. On Days 2 and 6, renal biopsies, as well as glomerular isolates, urine and blood samples were taken to compare vardenafil- and placebo-treated groups during the course of disease.

Results. Small amounts of PDE-5 were detected in healthy kidneys, but induced in a typical mesangial pattern during disease (by IHC and WB). Specific PDE-5 inhibition resulted in increased glomerular levels of cGMP. Treated animals demonstrated inhibition of MC proliferation and matrix accumulation while renal function and influx of inflammatory cells were not affected. Due to PDE-5 inhibition, the endogenous TGF-β-activating protein TSP-1 and the TGF-β-signalling protein p-smad-2/3 were decreased suggesting this as an antifibrotic mechanism of action of vardenafil in this model.

Conclusion. Considering the availability and safety profile of vardenafil, the beneficial antiproliferative and antifibrotic effect in experimental glomerulonephritis may potentially be applicable to the treatment of mesangial proliferative glomerulonephritis in man.

Keywords: anti-Thy1 model; matrix expansion; PDE-5 inhibition; TGF-β; TSP-1

Received for publication: 25. 2.08
Accepted in revised form: 19. 5.08


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