Differential expression of MMP-2/MMP-9 and potential benefit of an MMP inhibitor in experimental acute kidney allograft rejection.
Acute cellular allograft rejection is characterized by leukocyte invasion and tissue destruction, associated with qualitative and quantitative alterations in the extracellular matrix (ECM) compartment. Metabolism of ECM proteins is mainly regulated by matrix metalloproteinases (MMP), that are zinc depended endoproteinases. MMP, especially basement membrane degrading MMP-2 and MMP-9, also facilitate tissue invasion of leukocytes. In addition, MMP-2 exerts a direct pro-inflammatory effect upon glomerular mesangial cells. Therefore, the investigation of the role of MMP in transplant rejection may lead to novel approaches in the therapy of rejection processes. To our knowledge, this is the first study of acute allograft rejection, formally addressing expression and activity of MMP, including the effect of a MMP inhibiting agent. For our studies, we used the orthotopic kidney allograft model in the stringent Dark Agouti-to-Lewis rat strain combination. Animals were divided into four groups: group A, healthy untreated Lewis rats (n=3); group B, sham operated Lewis rats (n=3); group C, transplanted Lewis rats treated with vehicle solution only (n=12); group D, transplanted Lewis rats treated with MMP inhibitor BB-94 (n=12). Respective animals were treated once daily intraperitonealy with BB-94 (30 mg/kg) or vehicle solution only. Treatment lasted from the third preoperative day until the end of the experiment, the time of severe rejection at day +7. Acute kidney allograft rejection led to alterations in the expression and activity of MMP. Overall MMP activity slightly increased despite severe destruction of kidney histology. The MMP inhibitor BB-94 successfully inhibited MMP activity to a high extent. MMP expression did not show uniform findings, since acute rejection led to differential expression of MMP-2 and MMP-9. During the rejection process, MMP-9 showed a small but significant increase, whereas MMP-2 production decreased substantially. Interestingly, BB-94 was able to keep proteinuria at a low level in transplanted animals. In conclusion, MMP-especially MMP-9-appear to represent new mediators involved in acute kidney transplant rejection.
Ermolli
Monica
M
Division of Nephrology and Hypertension, Inselspital Bern, CH-3010, Bern, Switzerland.
Schumacher
Martin
M
Lods
Nadège
N
Hammoud
Mahmoud
M
Marti
Hans Peter
HP
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006084:Graft Rejection / Q000201:enzymology*; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000187:drug effects; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9