Renal transplantation is the best therapy for end stage renal failure. It improves life quality and survival time of recipients compared to other therapies such as hemodialysis. In the past decades,with the increasing use of new kinds of immuno-suppressants and improvment of HLA matching, the incidence of early acute rejection in renal transplantation decreased significantly, while long-term renal graft survival remain to improve. AMR is a main immune cause of long-term renal graft survival. The histopathological changes of renal allograft morphologically appear as renal interstitial fibrosis, tubular atrophy and thickening of glomerular basement membrane; and/or diffuse mononuclear cell infiltration and fibrosis in interstitium; partial tubular atrophy, lumen expansion, arrange irregularly, thickening of basement membrane, partial medullary ductal ectasia of kidney allograft, common protein casts; focal and segmental glomerulosclerosis, even if thoroughly hyaline arteriolosclosis, mesangial region broading, chickening of basement membrane, visible tram line shadow (Figure
2C), arterial wall intima proliferation, narrowing of artery, the intimal concentric and fibrous proliferation, stricture or blocking of lumen of interlobular artery or its branches (Figure
2B). The clinical manifestations were slowly creeping upward of serum creatinine, proteinuria and hypertention, eventually developing into ESRD, due to mesangial matrix sediment, thickening of glomerular basement membrane and renal interstitial fibrosis or tubular atrophy. The pathological chages involved into the disorder of ECM synthesis and break down. The synthesis of ECM was influenced by TGF and other cytokines, and the breakdown of ECM was influenced by MMPs and TIMPs.
MMPs, also called as collagenase IV or collagenase A, belong to one group of Zn dependent proteinases leading specific degradation of ECM, and one of their primary functions is to break down collagen IV. Collagen IV is the main constituent in glomerular basement membrane. MMP-2 with relative molecule weight 72,000, a kind of collagenase A, may degrade collagen IV
. The disorder of MMP-2 expression might induce changes in tubular basement membrane structure, thus resulting to renal tubular epithelial cell transdifferentiation with tubular atrophy, fibrosis and renal dysfunction
. MMP-2 participates in the degradation of ECM, however TIMP-1 regulates its activity. MMP-2 and TIMP-1 play important roles in regulating the synthesis and degradation of ECM.
The results of our present study suggested that MMP-2 and TIMP-1 were weakly expressed in normal kidney tissue, but their expression was upregulated in AMR. MMP-2 was mainly expressed in IF/TA-I group, and its expression was decreasing along with the aggravation of pathological classification, however the expression of TIMP-1 was increasing along with the aggravation of the pathological classification of IF/TA, simultaneously renal function was gradually aggravated and the level of Scr was increasing along with the pathological classification of IF/TA. The imbalance between MMP-2 and TIMP-1 might participate in the development of renal allograft fibrosis, so it is necessary to explore the mechanism how the imbalance between MMP-2 and TIMP-1 participates in renal interstitial fibrosis and tubular atrophy of AMR.
It was reported in literature that the expression of MMP-2 was decreased by 25mmol/L glucose, but the expression of TIMP-2, the special inhibitor of TIMP-1, was upregulated, which promoted ECM sidiment in the cultured human glomerular epithelial cells
. Berthier CC et al
 found that the expression of MMP-2 and its inhibitor TIMP-2 and mRNA of TGF increased significantly in chronic rejection animal model of Fisher and Lewis mouse. Experiment on unilateral ureteral obstruction model based on TIMP-1 transgenic mice found that the expression of TIMP-1 was upregulated, gelatinase activity was downregulated, ICAM-1 and TGF, collagenIand III were upregulated, renal interstitial fibrosis and macrophage infiltration aggravated, which suggest that TIMP-1 over expression might paiticipate in renal interstitial fibrosis and involve in the course of inflammatory reaction
. Wagrowska- Danilewicz et al
 found that the expression of both MMP-2 and TIMP-1 were upregulated in reanal allografts of 17 chronic allograft nephropathy patients compared to renal tissue of 11 normal controls, which suggest the remodeling of impaired renal structure have correlation with the regulation imbalance of MMP-2 and TIMP-1. The expression of TIMP-1 was downregulated, while the mRNA and protein expression and activities of MMP-2 and MMP-9 were enhanced after treatment with benazapril and all-trans retinoic acid (ATRA) in Wistar rat model of glomerular sclerosis compared to normal group
. The results of above studies suggest the ATRA exerts protection role by downregulate the expression of TIMP-1 and upregulate the mRNA expression and activity of MMP-2 and MMP-9, regulate the balance of the ratio of MMPs and TIMPs, and thus decrease ECM sediment. However it remains a question which needs further study that how to inhibit the activity of TGF, keep the balance of the activities of MMPs and TIMPs, retard ECM over sediment and improve renal allograft function.
If further researches may determine the pathogenesis of how the imbalance of MMP-2/TIMP-1 participates in AMR, then it might be the target of avoiding chronic renal allograft dysfunction to regulate the expression and activities of MMP-2 and TIMP-1.