title: Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.
abstract: BACKGROUND
  Thy-1.1 transgenic mice develop hypercellular focal and segmental glomerulosclerosis (FSGS) lesions that mimic human collapsing FSGS, in 7 days after injection with anti-Thy-1.1 antibodies. These lesions consist of proliferating parietal epithelial cells (PECs). We questioned whether the angiotensin converting enzyme inhibitor (ACE), captopril, could prevent the development of FSGS and if protection is related to the timing of drug administration.
  
  
  METHODS
  First, we compared the effect of captopril treatment with angiotensin II-(ANGII) independent antihypertensive therapy (triple therapy). Second, we tested the effects of captopril administered over four different time intervals: days -7 to 0 (Ca-7>0), days -7 to 7 (Ca-7>7), days 0-7 (Ca0>7) and days 3-7 (Ca3>7) (day 0 being the day of injection of the antibody).
  
  
  RESULTS
  In anti-Thy-1.1 injected control (C) mice we observed dedifferentiation and activation of podocytes, reflected by loss of ASD33 and increased expression of desmin, followed by a marked accumulation of PECs forming hypercellular lesions. PECs showed an increased expression of connective tissue growth factor (CTGF). Triple therapy or captorpil pre-treatment (Ca-7>0) had no significant effect on albuminuria or FSGS. In contrast, Ca0>7 and Ca3>7 treatment significantly lowered albuminuria and attenuated development of FSGS. The latter two treatments attenuated loss of ASD33 expression by podocytes but could not prevent increased desmin expression. In addition, these treatments reduced CTGF expression by PECs and prevented PEC proliferation.
  
  
  CONCLUSIONS
  ACE inhibition, but not triple therapy, prevents the development of FSGS, suggesting an important role for ANGII. ACE inhibition has a protective effect even when started 3 days after the initial podocyte insult, which is probably related to the ability of ACE-inhibition to block PEC activation and proliferation.
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. b.smeets@pathol.umcn.nl
authors.forename: Bart
authors.initials: B
authors.lastname: Smeets
authors.forename: Mark L M
authors.initials: ML
authors.lastname: Steenbergen
authors.forename: Henry B P M
authors.initials: HB
authors.lastname: Dijkman
authors.forename: Kiek N
authors.initials: KN
authors.lastname: Verrijp
authors.forename: Nathalie A J M
authors.initials: NA
authors.lastname: te Loeke
authors.forename: Jan
authors.initials: J
authors.lastname: Aten
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Steenbergen
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D005923:Glomerulosclerosis, Focal Segmental / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000235:genetics*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D018800:Thy-1 Antigens; D007703:Peptidyl-Dipeptidase A