High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells: possible role in mesangium accumulation

Aims/hypothesis. High glucose concentration decreases the degradation of me sangium matrix, an action substantially mediated by a reduction in the acti vities of the matrix metalloproteinases (MMPs). Metalloproteinase-2 is uniq ue in that it is activated on the cell surface by one of the membrane type metalloproteinases (MT1-MMP), a process involving complex interactions with tissue inhibitor of metalloproteinase-2. The aim of this study was investi gate the effects of glucose concentration on mesangial cell gene expression of MT1-MMP and its ability to modulate the activation of metalloproteinase -2. Methods. Gene expression was determined using competitive RT-PCR, protein e xpression of MMP-2 was measured by western blot and its activation by zymog raphy. Concanavalin A, known to increase MT1-MMP expression was added in so me experiments. Results. High glucose concentration decreased MT1-MMP gene expression (11.5 2 +/- 1.63 and 4.84 +/- 0.72 amol/mu g RNA, 5 vs 25 mmol/l glucose, respect ively) and decreased activation of MMP-2 by 30 % despite a twofold increase in gene expression of MMP-2. Concanavalin A increased expression of MT1-MM P and activation of MMP-2. Irrespective of whether MMP-2 was from endogenou s or exogenous source there was an excellent correlation between the MT1-MM P expression and degree of MMP-2 activation, whereas the gene expression of TIMP-2 was not significantly altered by high glucose concentration or conc anavalin A. Conclusions/interpretation. Our results indicate that in a high glucose mil ieu, suppression of MT1-MMP expression could explain the low MMP-2 activity in the presence of high MMP-2 expression. This process could contribute to the mesangium matrix accumulation in diabetic nephropathy.