title: Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats.
abstract: BACKGROUND
  Chronic allograft nephropathy (CAN) belongs to the major causes of long-term kidney allograft failure. One of the histologic hallmarks of CAN is interstitial fibrosis, influenced by matrix metalloproteinases (MMPs) that are controlling extracellular matrix (ECM) degradation. Whether MMPs affect the development and progression of CAN is not clear so far. To analyze the role of MMPs in CAN, we investigated the effects of an early and a late application of BAY 12-9566, an inhibitor of MMP-2, -3, and -9 on the development and progression of CAN in a rat kidney-transplantation model.
  
  
  METHODS
  Fisher kidneys were orthotopically transplanted into Lewis recipients that were treated with BAY 12-9566 (15 mg/kg per day) or vehicle either for the first 10 days after transplantation (early treatment) or from week 12 to week 20 after transplantation (late treatment). Proteinuria was analyzed every 4 weeks up to week 20 after transplantation when kidney grafts were removed for further analysis.
  
  
  RESULTS
  Early MMP-inhibition resulted in a significantly reduced 24-hour protein excretion that was paralleled by a lower grade of CAN after 20 weeks. However, late MMP inhibition starting at week 12 after transplantation resulted in significantly higher proteinuria and a higher grade of CAN as compared with controls. Furthermore, transforming growth factor-beta and platelet-derived growth factor-B chain mRNA levels were significantly increased in these animals.
  
  
  CONCLUSIONS
  Inhibition of MMPs early after transplantation reduced the development and progression of CAN but promoted CAN if initiated at later stages. Thus, MMPs are involved in the development and progression of CAN.
authors.affiliation: Department of Nephrology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Yousheng
authors.initials: Y
authors.lastname: Yao
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
authors.forename: Balazs
authors.initials: B
authors.lastname: Antus
authors.forename: Peter
authors.initials: P
authors.lastname: Hamar
authors.forename: Shanying
authors.initials: S
authors.lastname: Liu
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds; D001794:Blood Pressure; D001835:Body Weight; D002908:Chronic Disease; D003401:Creatine / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D006084:Graft Rejection / Q000150:complications* / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009401:Nephrosis / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D009930:Organic Chemicals / Q000494:pharmacology; D010654:Phenylbutyrates; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C113281:Bay 12-9566; D020782:Matrix Metalloproteinases; D003401:Creatine