title: Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome.
abstract: BACKGROUND
  Alport syndrome (AS) is a common hereditary cause of end-stage renal failure in adolescence due to defects in type IV collagen genes. Molecular genetics allows early diagnosis, however, no preventive strategy can be offered. Using the COL4A3 -/- mouse, an animal model for human AS, we evaluated therapy with ramipril in mice.
  
  
  METHODS
  One hundred and twenty-two Alport-mice were treated with 10 mg/kg/day ramipril added to drinking water. Proteinuria, serum-urea and lifespan were monitored. Renal matrix was characterized by immunohistochemistry, light- and electron microscopy, and Western blot.
  
  
  RESULTS
  Untreated COL4A3 -/- mice died from renal failure after 71 +/- 6 days. Early therapy starting at four weeks of age and continuing to death delayed onset and reduced the extent of proteinuria. Uremia was postponed by three weeks in treated animals. Lifespan increased by more than 100% to 150 +/- 21 days (P < 0.01). In parallel, decreased deposition of extracellular matrix and lessened interstitial fibrosis as well as reduced amounts of renal transforming growth factor-beta1 (TGF-beta1) could be demonstrated. Late therapy starting at seven weeks decreased proteinuria, however, lifespan did not increase significantly.
  
  
  CONCLUSIONS
  The results indicate an antiproteinuric and antifibrotic nephroprotective effect of ramipril in COL4A3 -/- mice is mediated by down-regulation of TGF-beta1. This effect in mice is enhanced by initiation of therapy during pre-symptomatic disease. The data in COL4A3 -/- mice as an animal-model for Alport syndrome suggest that ramipril might as well delay renal failure in humans with AS. Early diagnosis and preemptive treatment also may be crucial in humans.
authors.affiliation: Medical Faculty University of Cologne, Department of Internal Medicine I, Cologne General Hospital, Merheim Medical Center, Cologne, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Koepke
authors.forename: Jeannine
authors.initials: J
authors.lastname: Kuck
authors.forename: Michael
authors.initials: M
authors.lastname: Reiner
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Neil
authors.initials: N
authors.lastname: Smyth
authors.forename: Eckhard
authors.initials: E
authors.lastname: Schulze-Lohoff
authors.forename: Manfred
authors.initials: M
authors.lastname: Weber
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001485:Basement Membrane / Q000473:pathology; D024141:Collagen Type IV / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011507:Proteinuria / Q000517:prevention & control; D017257:Ramipril / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1; D014511:Uremia / Q000517:prevention & control
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001324:Autoantigens; D024141:Collagen Type IV; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C057112:type IV collagen alpha3 chain; D017257:Ramipril