Περίληψη:
Thickening of the tubular basement membrane (TBM) occurs in diabetic
nephropathy, but the effects of high glucose on the functional aspects
of proximal tubular epithelial cells are not clearly understood. In the
present study, we examined the effects of elevated glucose
concentrations on (a) integrin expression by human proximal tubular
epithelial cells (HK-2) and integrin-mediated interactions with type IV
collagen (coIIV) and laminin, major components of TBM; (b) the
expression of matrixins/matrix metalloproteinases (MMPs), which is
regulated by integrins; and (c) the expression of tissue inhibitors of
metalloproteinases (TIMPs). HK-2 cells cultured in 25 mM glucose
underwent a reduction of the expression of alpha(3), beta1, alphavbeta3,
and alpha5 integrin subunits, with a concomitant increase of the alpha2
subunit, compared with cells grown in 5 mM glucose. Adhesion experiments
demonstrated that high glucose led to increased cell adhesion on either
coIIV or laminin. Experiments of competition of adhesion using
anti-integrin antibodies indicated that HK-2 cells in 5 mM glucose used
mainly alphavbeta3 and alpha5beta1 integrins to adhere to coIIV, whereas
in 25 mM glucose they additionally used alpha2beta1. In the case of
laminin, a beta1-mediated adhesion was observed when HIK-2 cells were in
5 mM glucose, whereas in 25 mm glucose, alpha2beta1 and alphavbeta3 were
also involved. Elevated glucose concentrations resulted in decreased
expression of MMP-9 and MMP-2, whereas an increase in TIMP-1 and a
decrease in TIMP-2 expression were observed. We also examined which
integrins mediated the expression and secretion of matrixins MMP-2 and
MMP-9. Ligation of alpha3beta1 with mAbs resulted in induction of MMP-2
expression and secretion, whereas antibody ligation of alphavbeta3 led
to down-regulation of MMP-9. The above data implicate integrins of
proximal tubular epithelial cells in the regulation of MMPs and in the
development of TBM thickening in diabetic nephropathy.
Συγγραφείς:
Karamessinis, PM
Tzinia, AK
Kitsiou, PV
Stetler-Stevenson,
WG
Michael, AF
Fan, WW
Zhou, B
Margaritis, LH and
Tsilibary, EC
