Sv. Mclennan et al., High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells: possible role in mesangium accumulation, DIABETOLOG, 43(5), 2000, pp. 642-648
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.