Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats.
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.
Lutz
Jens
J
Department of Nephrology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Yao
Yousheng
Y
Song
Erwei
E
Antus
Balazs
B
Hamar
Peter
P
Liu
Shanying
S
Heemann
Uwe
U
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
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