Changes in Matrix Metalloproteinases and Their Inhibitors in Kidney Transplant Recipients

Abstract

Objectives: Chronic allograft nephropathy remains one of the main causes of late graft loss after kidney transplant owing to multifactorial development of kidney scarring. Chronic allograft nephropathy is characterised by an excess accumulation of extracellular matrix. A key system regulating extracellular matrix homeostasis are matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. This study sought to determine if a change in the matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases system contributes to chronic allograft nephropathy-associated progressive kidney scarring. Materials and Methods: Examination of sequential renal biopsies was done at implantation, acute rejection, and subsequent chronic allograft nephropathy. In situ localisation of matrix metalloproteinase activity was assessed with a high-resolution in situ zymography technique using gelatin and collagen 1 substrates. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were localised using immunohistochemistry. Results: In situ zymography showed over a 50% reduction in matrix metalloproteinase activity against both collagen 1 and gelatin substrates in chronic allograft nephropathy biopsies. A similar loss of matrix metalloproteinase activity was seen in the glomerular and tubulointerstitial compartments.Immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were observed intracellularly in mesangial and tubular epithelial cells. Matrix metalloproteinases-1, -2, -3, and -9 were significantly reduced in acute rejection and later in chronic allograft nephropathy. However, glomerular matrix metalloproteinases 1 and 9 and tubulointerstitial matrix metalloproteinase-2 were reduced at implantation. Tissue inhibitors of matrix metalloproteinase-2 and -3 were elevated from implantation onwards. We were unable to stain reproducibly for tissue inhibitors of matrix metalloproteinase-1. Conclusions: Kidney scarring underlying chronic allograft nephropathy is associated with a reduction in matrix metalloproteinases activity that may be due to reduced expression of matrix metalloproteinases -1, -2, -3, and -9, and upregulation of tissue inhibitors of matrix metalloproteinases -2 and -3. Some of these changes originate from implantation.

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“…Wang et al have shown that TIMP-3 protects the cells from damage, whereas TIMP-2 appears to promote injury through matrix metalloproteinase activation [ 32 ]. Similarly, research studies in renal transplant allografts show that matrix metalloproteinase activity is important in mediating scarring in chronic allograft nephropathy [ 33 ].…”

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“…While TIMP-3 is required for optimal response to renal injury, TIMP-2 appears to promote disease progression through the activation of matrix metalloproteinase and triggering of tubulointerstitial fibrosis and injury. Similarly, research studies in renal transplant allografts show that matrix metalloproteinase activity is important in mediating scarring in chronic allograft nephropathy [ 37 ].…”

Ο Ρόλος Των Μεταλλοπρωτεϊνασών-2 Και -9 Στην Αθηροσκλήρωση Των Ασθενών Με Χρόνια Νεφρική Νόσο

“…Η έκφραση των TIMPs αυξάνεται από κυτταροκίνες (IL-1,-6,-11), αυξητικούς παράγοντες (TGF-β, Vascular Endothelial Growth Factor -VEGF) και ορμόνες39,40 . Η ισορροπία MMPs/TIMPs είναι ιδιαίτερα κρίσιμη για την εύρυθμη αναδιαμόρφωση των ιστών και η διαταραχή της σχέσης αυτής φαίνεται να εμπλέκεται σε πολλές παθολογικές διεργασίες, όπως αθηροσκλήρωση, ίνωση, νεοαγγειογένεση όγκων και μετάσταση[39][40][41][42][43][44][45][46][47][48][49] . Αρχικά θεωρήθηκε ότι οι MMPs αποδομούν μόνο τις πρωτεΐνες της ECM, κυρίως το col-IV, κύριο συστατικό των αγγείων και της BM, το οποίο διαδραματίζει κυρίαρχο ρόλο στην έναρξη και εξέλιξη της νεφρικής νόσου, καθώς και στην αθηροσκλήρωση24,42,43 .…”