TY - JOUR
T1 - Advanced glycation end products decrease mesangial cell MMP-7
T2 - A role in matrix accumulation in diabetic nephropathy?
AU - Mclennan, Susan V.
AU - Kelly, D. J.
AU - Schache, M.
AU - Waltham, Mark
AU - Dy, V.
AU - Langham, R. G.
AU - Yue, D. K.
AU - Gilbert, Richard E
PY - 2007/8
Y1 - 2007/8
N2 - Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-β (TGF-β) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-β.
AB - Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-β (TGF-β) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-β.
KW - Advanced glycation end product
KW - Diabetic nephropathy
KW - Extracellular matrix
KW - Fibronectin
KW - Mesangial cells
UR - http://www.scopus.com/inward/record.url?scp=34547814720&partnerID=8YFLogxK
U2 - 10.1038/sj.ki.5002357
DO - 10.1038/sj.ki.5002357
M3 - Article
C2 - 17554258
AN - SCOPUS:34547814720
SN - 0085-2538
VL - 72
SP - 481
EP - 488
JO - Kidney International
JF - Kidney International
IS - 4
ER -