PDE-5 inhibition impedes TSP-1 expression, TGF-beta activation and matrix accumulation in experimental glomerulonephritis.
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-beta-activating protein TSP-1 and the TGF-beta-signalling protein p-smad-2/3 were decreased suggesting this as an antifibrotic mechanism of action of vardenafil in this model.


CONCLUSIONS
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.
Hohenstein
Bernd
B
Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany. bernd.hohenstein@rzmail.uni-erlangen.de
Daniel
Christoph
C
Wittmann
Sandra
S
Hugo
Christian
C
D000818:Animals; D000911:Antibodies, Monoclonal; D001706:Biopsy; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005921:Glomerulonephritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
D000911:Antibodies, Monoclonal; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D013450:Sulfones; D019700:Thrombospondin 1; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP