Renal transplant fibrosis correlates with intragraft expression of tissue inhibitor of metalloproteinase messenger RNA.
BACKGROUND
Chronic renal allograft nephropathy is characterized by an abnormal accumulation of extracellular matrix proteins in the glomeruli and tubulo-interstitium. The aim of this study was to determine the relationship between intragraft expression of the genes controlling the accumulation of extracellular matrix and the development of chronic renal allograft nephropathy in human renal transplants.


METHODS
Forty renal allografts with stable renal function were biopsied 6 months after transplantation. Single glomeruli were plucked from the surface of these protocol biopsies and total messenger RNA (mRNA) was extracted. Reverse transcriptase-polymerase chain reaction was used to study the intragraft expression of several fibrosis-associated genes (collagen III, collagen IValpha2, matrix metalloproteinase (MMP) 2, tissue inhibitors of metalloproteinases (TIMPs) 1 and 2, tenascin and transforming growth factor (TGF) beta1). The level of tubulo-interstitial fibrosis was measured by quantitative immunostaining of collagen III.


RESULTS
There were positive correlations between the level of tubulo-interstitial collagen III immunostaining and intragraft expression of the genes for TIMP-1 (rs= 0.70, P < 0.02) and TIMP-2 (rs = 0.59, P < 0.02). Interstitial fibrosis was also strongly correlated with the levels of TGF-beta mRNA (rs = 0.67, P < 0.002). Finally, TIMP-1 expression increased with TGF-beta expression (rs = 0.77, P < 0.002).


CONCLUSIONS
Failure of extracellular matrix degradation may be an important molecular mechanism in the pathogenesis of chronic renal allograft damage.
Nicholson
M L
ML
University Department of Surgery, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. mln2@leicester.ac.uk
Waller
J R
JR
Bicknell
G R
GR
D001707:Biopsy, Needle; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D011183:Postoperative Complications / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D014184:Transplantation, Homologous
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases