title: Following specific podocyte injury captopril protects against progressive long term renal damage.
abstract: BACKGROUND
  Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model.
  
  
  METHODS
  We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group.
  
  
  RESULTS
  After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05).
  
  
  CONCLUSIONS
  Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury.
authors.affiliation: Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK.
authors.forename: Yu S
authors.initials: YS
authors.lastname: Zhou
authors.affiliation: Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK.
authors.forename: Ihmoda A
authors.initials: IA
authors.lastname: Ihmoda
authors.affiliation: Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Phelps
authors.affiliation: Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK.
authors.forename: Christopher Os
authors.initials: CO
authors.lastname: Bellamy
authors.affiliation: Centre for Inflammation Research, Renal Medicine, University of Edinburgh and Royal Infirmary, Edinburgh, EH16 4SB, UK.
authors.forename: A Neil
authors.initials: AN
authors.lastname: Turner
keywords: ACEi; angiotensin; podocyte; proteinuria