Transglutaminases (Tg) are a family of calcium-dependent enzymes that catalyse the crosslinking of polypeptide chains, including those of extracellular matrix (ECM) proteins, through the formation of e(v-glutamyl) lysine bonds. This leads to the formation of protein polymers that are highly resistant to degradation. Consequently, tissue Tg (tTg) has been associated with ECM protein deposition in fibrotic diseases such as pulmonary fibrosis and atherosclerosis. hi this study, we have investigated the involvement of tTg in the development of kidney fibrosis in adult male Wistar rats submitted to subtotal nephrectomy (SNx). Groups of 4 to 6 rats were sacrified on days 7, 30, 90, and 120 after SNx. As previously described these rats developed progressive glomerulosclerosis and tubulo-interstitial fibrosis. The tissue level of e(y-glutamyi) lysine crosslink (as determined by exhaustive proteolytic digestion followed by cation exchange HPLC) increased from 347 + 94 pmol/mg protein (M.+S.E.M.) in controls to 1324 + 143 pmol/mg 90 days after SNx (p<0.01). Levels of crosslink correlated well with the renal fibrosis score throughout the 120 observation days (r=0.78, pO.Ol). Tissue homogenates showed no significant change in overall tTg activity (14C-putrescine incorporation assay) during this period. Immunohistochemistry demonstrated that this large increase in crosslink was predominantly in the cytoplasm of tubular cells and that these cells also showed a large increase in tTg antigen. Some of the cells high in crosslink and tTg displayed the morphology of a cell undergoing apoptosis, although these cells did not frequently show DNA cleavage (in-situ end labelling) typically associated with apoptosis. We noted an association between tTg, crosslink and renal scarring in rats submitted to SNx. We would like to postulate a role for tissue transglutamrnase in the development of experimental renal fibrosis.
|Original language||English (US)|
|Journal||Biochemical Society Transactions|
|State||Published - Jan 1 1996|
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