title: The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids.
abstract: BACKGROUND
  Experimental aristolochic acid nephropathy (AAN), characterized by interstitial fibrosis, tubular atrophy, and chronic renal failure, was reported after 35-day injections of aristolochic acids (AA) to salt-depleted male Wistar rats. The link between renal fibrosis and the renin-angiotensin system (RAS) in this model remains unknown.
  
  
  METHODS
  We investigated the impact of sodium diets (low and normal), of RAS inhibition with enalapril (ENA) alone, or combined with candesartan (CSN) for 35 days, and ENA + CSN for 65 days on AAN development. At the end of each observation period, blood pressure and renal angiotensin-converting enzyme activity were measured, as well as renal functional impairment (plasma creatinine increase, proteinuria) and histologic lesions (interstitial fibrosis, monocytes/macrophages infiltration, myofibroblasts collagens type I and IV, proliferating cells).
  
  
  RESULTS
  Sodium intake did not modify renal functional and morphologic impairment induced by AA. The RAS blockade by ENA or ENA + CSN in rats receiving AA did not result in any statistical difference in terms of renal failure, proteinuria, and interstitial fibrosis on day 35 or 65. On day 35, the monocytes/macrophages infiltration was significantly decreased by two-fold when ENA (P < 0.01) or ENA + CSN (P < 0.01) was given from day 0.
  
  
  CONCLUSIONS
  Our data demonstrate that RAS modulation by salt depletion and pharmacologic blockade do not influence renal failure and interstitial fibrosis in the rat model of AAN. We suggest that pathways of interstitial renal fibrosis may be independent of RAS at least in some conditions.
authors.affiliation: Laboratory for Research on Peptide Metabolism, Faculty of Medicine, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. fdebelle@ulb.ac.be
authors.forename: Frédéric D
authors.initials: FD
authors.lastname: Debelle
authors.forename: Joëlle L
authors.initials: JL
authors.lastname: Nortier
authors.forename: Cécile P
authors.initials: CP
authors.lastname: Husson
authors.forename: Eric G
authors.initials: EG
authors.lastname: De Prez
authors.forename: Anne R
authors.initials: AR
authors.lastname: Vienne
authors.forename: Katja
authors.initials: K
authors.lastname: Rombaut
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Salmon
authors.forename: Monique M
authors.initials: MM
authors.lastname: Deschodt-Lanckman
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanherweghem
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D034341:Aristolochic Acids; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D004357:Drug Synergism; D004656:Enalapril / Q000494:pharmacology*; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D034341:Aristolochic Acids; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; C081643:candesartan