title: Effect of mycophenolate mofetil on glomerulosclerosis and renal oxidative stress in rats.
abstract: OBJECTIVE
  Mycophenolate mofetil (MMF) is known to attenuate glomerulosclerosis in experimental models of renal failure. We investigated whether this is mediated by reduction of oxidative stress.
  
  
  METHODS
  Effects of MMF on oxidative stress are studied in an experimental rat model (NA model) involving unilateral nephrectomy and two intravenous injections with adriamycin (2 mg/kg). Rats are sacrificed after 2 and 6 weeks. Glomerulosclerosis and tubulointerstitial lesions are demonstrated by histological techniques. Presence of macrophages/monocytes (ED1) and myofibroblasts (alpha-SMA) is demonstrated by immunohistochemistry. Oxidative stress is evaluated by enzymatic measurements (AOE), spectrofluorometry (TBARS), immunohistochemistry (MDA and HNE) and histology (ferric iron deposition).
  
  
  RESULTS
  The NA model shows proteinuria, hypercholesterolemia, beginning glomerulosclerosis, tubulointerstitial sclerosis and tubular dilatation, glomerular, periglomerular and interstitial presence of alpha-SMA and increased presence of macrophages/monocytes after 6 weeks. Oxidative stress in renal cortex is apparent (increased cortex TBARS concentration, increased glomerular presence of MDA and HNE, decreased activity of antioxidant enzymes, ferric iron deposition in proximal tubules) after 6 weeks. MMF administration results in a decrease of glomerulosclerosis, interstitial sclerosis, glomerular and periglomerular expression of alpha-SMA and the number of ED1-positive cells in tubulointerstitium and glomeruli. Proteinuria and cholesterolemia are not decreased. TBARS level, and activities of catalase, Mn and Cu/Zn superoxide dismutase as well as the presence of ferric iron in the proximal tubules are not changed by MMF treatment. Cortex activity of glutathione peroxidase returns to normal.
  
  
  CONCLUSIONS
  MMF has a favorable effect on glomerular and interstitial fibrosis in the NA model of kidney disease, but not on proteinuria and cholesterolemia. Improvement of fibrosis cannot be explained by major changes in oxidative stress or antioxidant defense.
authors.affiliation: Department of Human Anatomy, Vrije Universiteit Brussel, Brussels, Belgium. cvdbrand@vub.ac.be
authors.forename: Christiane
authors.initials: C
authors.lastname: Van den Branden
authors.forename: Bart
authors.initials: B
authors.lastname: Ceyssens
authors.forename: Marina
authors.initials: M
authors.lastname: Pauwels
authors.forename: Greet
authors.initials: G
authors.lastname: Van Wichelen
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Heirman
authors.forename: Ni
authors.initials: N
authors.lastname: Jie
authors.forename: Dierik
authors.initials: D
authors.lastname: Verbeelen
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000941:Antigens / Q000276:immunology; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000737:chemistry / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D000941:Antigens; D009173:Mycophenolic Acid