title: Direct renin inhibition in a rat model of chronic allograft injury.
abstract: BACKGROUND
  Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers (ARBs) slow the progression of various chronic kidney diseases and chronic allograft dysfunction. RAS inhibition can be achieved also by directly blocking renin upstream from ACE. However, direct renin inhibition can have additional effects since formation of renoprotective Ang II breakdown products such as angiotensin (Ang) (1-7) that are produced by ACE2 are also inhibited.
  
  
  METHODS
  Using a Fischer-to-Lewis renal transplantation model, the effect of the renin inhibitor aliskiren (10 mg/kg/day) was assessed on the development of chronic allograft dysfunction compared with vehicle treatment and Ang II receptor blockers candesartan.
  
  
  RESULTS
  Aliskiren had no effect on renal function (proteinuria, creatinine clearance) or on renal morphological changes (glomerulosclerosis collagen deposition, myofibroblast accumulation and macrophage infiltration) compared with the vehicle- and candesartan-treated animals determined 24 weeks after transplantation. On the other hand, atrophy of tubular cells was significantly attenuated. Candesartan reduced both proteinuria and structural injury of the kidney. In aliskiren-treated animals reduced serum Ang II and Ang (1-7) levels were detected, whereas the level of urine angiotensinogen was unchanged.
  
  
  CONCLUSIONS
  The renin inhibitor aliskiren does not slow the progression of chronic allograft dysfunction. We suggest that the lack of protection might be due to reduced formation of the protective Ang II breakdown products such as Ang (1-7) or due to unchanged intrarenal RAS activity demonstrated by urinary angiotensinogen levels.
authors.affiliation: Department of Nephrology, Klinikum Rechts der Isar, Munich, Germany.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Rusai
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmaderer
authors.forename: J J Rob
authors.initials: JJ
authors.lastname: Hermans
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.forename: Marcus
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D005650:Fumarates / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D010446:Peptide Fragments / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014184:Transplantation, Homologous; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000803:Angiotensin I; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005650:Fumarates; D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000092502:Renin Inhibitors; C446481:aliskiren; C118790:angiotensin I (1-7); C081643:candesartan