Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688.
BACKGROUND
Chronic renal disease substantially increases the risk of cardiovascular events and death. Vasopeptidase inhibitors are known to show a strong antihypertensive effect. In the present study, we investigated the nephroprotective potential of the vasopeptidase inhibitor AVE7688 beyond its antihypertensive effects in a mouse model of progressive renal fibrosis.


METHODS
COL4A3 -/- mice received 25 mg AVE7688 per kg body weight. Treatment was initiated in week 4 (early) and week 7 (late). Eight mice per group were sacrificed after 7.5 or 9.5 weeks, and serum levels of urea, systemic blood pressure, and proteinuria were measured. Renal tissue was investigated by routine histology, electron microscopy, immunohistochemistry, and Western blotting. Lifespan until death from renal fibrosis was monitored.


RESULTS
Lifespan of treated mice increased by 143% (early therapy) and by 53% (late therapy) compared to untreated animals (172 +/- 19 vs. 109 +/- 15 vs. 71 +/- 6 days, P < 0.01). Untreated COL4A3 -/- mice did not develop severe hypertension (mean systolic blood pressure 116 +/- 14 vs. 111 +/- 9 mm Hg in wild-type mice), and both therapies mildly reduced systemic blood pressure (107 +/- 13 and 105 +/- 14 mm Hg, data not significant). AVE7688 decreased proteinuria from 12 +/- 3 g/L in untreated mice to 2 +/- 1 g/L (early) and to 4 +/- 1 g/L (late therapy, P < 0.05), as well as serum-urea from 247 +/- 27 to 57 +/- 10 and to 105 +/- 20 mmol/L (P < 0.05). Extent of fibrosis, inflammation, and profibrotic cytokines was reduced by AVE7688 therapy.


CONCLUSIONS
The results indicate a strong nephroprotective effect of the vasopeptidase inhibitor in this animal model of progressive renal fibrosis. Besides the antihypertensive action of AVE7688, its antifibrotic, anti-inflammatory, and antiproteinuric effects demonstrated in the present study may serve as an important therapeutic option for chronic inflammatory and fibrotic diseases in man.
Gross
Oliver
O
Department of Internal Medicine I, Medical Faculty University of Cologne, Cologne General Hospital, Merheim Medical Center, Cologne, Germany. oliver.gross@uni-koeln.de
Koepke
Marie-Louise
ML
Beirowski
Bogdan
B
Schulze-Lohoff
Eckhard
E
Segerer
Stephan
S
Weber
Manfred
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001324:Autoantigens / Q000235:genetics; D001794:Blood Pressure; D024141:Collagen Type IV / Q000235:genetics; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000473:pathology; D005355:Fibrosis; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008017:Life Expectancy; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009394:Nephritis, Hereditary / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
C479877:AVE 7688; D000893:Anti-Inflammatory Agents; D001324:Autoantigens; C526318:CCN2 protein, mouse; D024141:Collagen Type IV; D006575:Heterocyclic Compounds, 3-Ring; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011355:Prodrugs; D011480:Protease Inhibitors; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C057112:type IV collagen alpha3 chain; D055513:Connective Tissue Growth Factor