Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy?
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-beta (TGF-beta) 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-beta.
McLennan
S V
SV
Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. sue@med.usyd.edu.au
Kelly
D J
DJ
Schache
M
M
Waltham
M
M
Dy
V
V
Langham
R G
RG
Yue
D K
DK
Gilbert
R E
RE
D000328:Adult; D000818:Animals; D000906:Antibodies; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D017077:Culture Media, Conditioned; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D006146:Guanidines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019278:Matrix Metalloproteinase 3; D053506:Matrix Metalloproteinase 10; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C004479:pimagedine