title: Enalaprilat directly ameliorates in vitro cyclosporin nephrotoxicity in human tubulo-interstitial cells.
abstract: OBJECTIVE
  Several recent studies have suggested that angiotensin-converting enzyme (ACE) inhibitors ameliorate chronic cyclosporin A (CyA) tubulo-interstitial disease by mechanisms independent of their antihypertensive effects. The aim of the present study was to determine whether ACE inhibition exerts a direct beneficial effect on the tubulo-interstitium in an in vitro model of chronic CyA nephropathy.
  
  
  METHODS
  Primary cultures of human proximal tubular cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 h to CyA in the presence or absence of enalaprilat. Parameters of tubulo-interstitial nephrotoxicity were then measured including collagen synthesis (proline incorporation), tubular viability and function (thymidine incorporation, lactate dehydrogenase release, and apical sodium-hydrogen exchange), and secretion of insulin-like growth factor I, transforming growth factor beta 1 (TGFbeta1), and platelet-derived growth factor.
  
  
  RESULTS
  CyA promoted CF collagen synthesis, PTC cytotoxicity (suppressed viability, growth and sodium transport), and tubulo-interstitial fibrogenic cytokine release (CF secretion of insulin-like growth factor I and PTC secretion of TGFbeta1 and platelet-derived growth factor). Enalaprilat completely reversed the stimulatory effects of CyA on CF collagen synthesis (CyA + enalaprilat 6.40 +/- 0.50% vs. CyA alone 8.33 +/- 0.56% vs. control 6.57 +/- 0.62% vs. enalaprilat alone 5.55 +/- 0.93%, p < 0.05) and PTC secretion of TGFbeta1 (0.71 +/- 0.11, 1.13 +/- 0.09, 0.89 +/- 0.07, and 0.67 +/- 0.09 ng/mg protein/day, respectively, p < 0.05). However, the other manifestations of CyA toxicity were not significantly reversed by concomitant enalaprilat administration.
  
  
  CONCLUSIONS
  ACE inhibition directly prevents CyA-induced interstitial fibrosis, but not proximal tubule cytotoxicity, independently of haemodynamic and systemic renin-angiotensin system effects. Renoprotection may be partially afforded by directly preventing the tubular secretion of TGFbeta1.
authors: Department of Renal Medicine, Princess Alexandra Hospital, Brisbane, Australia. johnsond@health.qld.gov.au
authors: D W
authors: DW
authors: Johnson
authors: H J
authors: HJ
authors: Saunders
authors: D A
authors: DA
authors: Vesey
authors: W
authors: W
authors: Qi
authors: M J
authors: MJ
authors: Field
authors: C A
authors: CA
authors: Pollock
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D017077:Culture Media, Conditioned; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D015773:Enalaprilat / Q000494:pharmacology*; D005347:Fibroblasts; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007672:Kidney Cortex / Q000166:cytology; D007687:Kidney Tubules, Proximal / Q000473:pathology; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017077:Culture Media, Conditioned; D016207:Cytokines; D007166:Immunosuppressive Agents; D000804:Angiotensin II; D016572:Cyclosporine; D003094:Collagen; D015773:Enalaprilat