Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

Abstract

In rats, tolerance to MHC-incompatible renal allografts can be induced by the administration of anti-donor class II Abs on the day of transplantation. In this study we explored the mechanisms involved in the maintenance phase of this tolerance by analyzing intragraft gene expression profiles by microarray in long-term accepted kidneys. Comparison of the gene expression patterns of tolerated to syngeneic kidneys revealed 5,954 differentially expressed genes (p < 0.05). Further analysis of this gene set revealed a key role for the wingless-type (WNT) signaling pathway, one of the pivotal pathways involved in cell regulation that has not yet been implicated in transplantation. Several genes within this pathway were significantly up-regulated in the tolerated grafts, particularly matrix metalloproteinase 7 (MMP7; fold change > 40). Analysis of several other pathway-related molecules indicated that MMP7 overexpression was the result of the noncanonical WNT signaling pathway. MMP7 expression was restricted to vascular smooth muscle cells and was specific to anti-class II Ab-induced tolerance, as it was undetectable in other models of renal and heart transplant tolerance and chronic rejection induced across the same strain combination. These results suggest a novel role for noncanonical WNT signaling in maintaining kidney transplant tolerance in this model, with MMP7 being a key target. Determining the mechanisms whereby MMP7 contributes to transplant tolerance may help in the development of new strategies to improve long-term graft outcome.

The C-Type Lectin-Like Receptor CLEC-1, Expressed by Myeloid Cells and Endothelial Cells, Is Up-Regulated by Immunoregulatory Mediators and Moderates T Cell Activation

“…in a model of anti-donor class II Ab administration in which was previously shown a high intragraft expression of IDO and Foxp3 (n ϭ 5; ‫,ء‬ p Ͻ 0.05; Fig. 1B) (13,22).…”

“…LEW.1W (RT1u) or LEW.1A (RT1a) rats served as heart donors, and LEW.1A rats served as recipients. For allograft tolerance models, LF15-0195 (20 days) (Fournier Laboratories) or antidonor class II Abs were administered to recipients as previously described (12,13). Chronic allograft rejections were induced by two donor blood transfusions (donor-specific transfusion (DST)) before transplantation or by CD40-Ig administration as previously described (8,14).…”

Three-dimensional culture using a radial flow bioreactor induces matrix metalloprotease 7-mediated EMT-like process in tumor cells via TGFβ1/Smad pathway

“…A431 tumor cells, cultured under 3D conditions, showed increased expression of MMP7 in both gene and protein levels as compared with the cells cultured under 2D conditions among several effectors in the E-cadherin shedding mechanisms (45). It has been substantiated that the TGFß1 signaling pathway can activate MMP7 expression and function directly or indirectly via LEF1 activation as previously reported (43,(47)(48)(49). Proteolytic degradation of E-cadherin at the cell surface by MMPs, such as MMP7 or -3, appears to be another powerful and important mechanism for disassembly of the adheren junction by which E-cadherin-mediated cell-cell adhesion can be ablated.…”

“…Slug up-regulation may be caused partly by Wnt signal activation, resulting in GSK-3ß inhibition (21,55). It is also predictable that MMP7 overexpression is promoted directly not only by Wnt/LEF1 (47), but also by the FGF2/AP1/STAT1/3 (56) pathway. Further studies will be necessary to demonstrate a more detailed cross-talk mechanism between TGF/Smad and Wnt/ß-catenin signaling.…”

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

“…MMP-7 seems to act as a novel screening marker for renal disease in lupus nephritis [265], cardiovascular alterations in CKD patients [266], and as a possible predictive marker of kidney transplant rejection [267]. Among potential MMP-7 inhibitors, doxycycline seems to be effective in decreasing the protein loss in urine of patients with glomerulonephritis [268] and diabetic nephropathy [269].…”