Modulation of matrix gelatinases and metalloproteinase‐activating process in acute kidney rejection

Changes in matrix metalloproteinase (MMP) activities would contribute to the accumulation of extracellular matrix during acute kidney allograft rejection. MMP‐2 and MMP‐9 and other gelatinolytic activities were examined in the rejected graft and the urine of a rat model of acute kidney rejection (orthotopic allotransplantation from a Buffalo donor to a Wistar‐Furth recipient) by either zymography or fluorescence assay. MMP‐2, membrane type 1 (MT1)‐MMP, and tissue inhibitor of metalloproteinase (TIMP)‐2 were also examined by immunodetection. The proMMP‐2 activity and protein level increased in the graft during rejection when compared with normal Buffalo kidney, whereas activated MMP‐2 decreased. TIMP‐2 protein levels were markedly decreased and MT1‐MMP proteolytic fragments (44‐40 kDa) were undetectable. This suggests an altered MT1‐MMP‐dependent processing of proMMP‐2 into active MMP‐2 due to a diminished TIMP‐2 level in acute kidney rejection. In the urine the overall gelatinolytic activity decreased considerably, although activity associated with an as yet unidentified 78‐kDa protein appeared 6 days after transplantation.