title: Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney.
abstract: BACKGROUND
  Myofibroblasts have been shown to play a pivotal role in the synthesis of extracellular matrix components in several animal models of renal fibrosis. The purpose of the present study was to investigate whether mycophenolate mofetil (MMF) reduces interstitial myofibroblast infiltration and collagen III deposition in 5/6 nephrectomized rats.
  
  
  METHODS
  Forty-five Wistar rats underwent 5/6 renal ablation and received by daily oral gavage either vehicle (N = 20) or MMF (N = 25) during the 60 days following surgery. Groups of five treated and five untreated rats were killed at two, four, and eight weeks after subtotal nephrectomy. Four untreated and three treated rats were killed at week 12, one month after treatment withdrawal. At the time of sacrifice, proteinuria, plasma, and urine creatinine were determined. Immunohistochemistry was performed on renal tissue for alpha-smooth muscle actin (alpha-SMA), a cytoskeletal marker of myofibroblasts, for type III collagen, and for proliferating cell nuclear antigen (PCNA). Moreover, in order to study the in vitro effects of MMF on fibroblast proliferation, rat fibroblasts were cultured in the presence or absence of mycophenolic acid (MPA).
  
  
  RESULTS
  At all periods studied, MMF treatment improved renal functional parameters and progressively decreased remnant kidney hypertrophy and glomerular volume increment. Proliferating cells in renal tubules, interstitium, and glomeruli, as well as interstitial myofibroblast infiltration and interstitial type III collagen deposition, were also significantly reduced by MMF treatment. In addition, MPA exhibited a dose-dependent inhibitory effect on in vitro proliferation of rat fibroblasts.
  
  
  CONCLUSIONS
  Reduction of interstitial myofibroblast infiltration may be an important event by which MMF significantly prevents renal injury following subtotal renal ablation. Thus, our results suggest that MMF could be useful to limit the progression of chronic renal disease toward end-stage renal failure.
authors.affiliation: Département de Néphrologie, Hôpital Edouard Herriot, Laboratoire de Physiologie de l'Environnement, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Badid
authors.forename: M
authors.initials: M
authors.lastname: Vincent
authors.forename: B
authors.initials: B
authors.lastname: McGregor
authors.forename: M
authors.initials: M
authors.lastname: Melin
authors.forename: A
authors.initials: A
authors.lastname: Hadj-Aissa
authors.forename: C
authors.initials: C
authors.lastname: Veysseyre
authors.forename: D J
authors.initials: DJ
authors.lastname: Hartmann
authors.forename: A
authors.initials: A
authors.lastname: Desmouliere
authors.forename: M
authors.initials: M
authors.lastname: Laville
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D007668:Kidney / Q000166:cytology* / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009392:Nephrectomy; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D003094:Collagen; D003404:Creatinine; D009173:Mycophenolic Acid