High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes.
Recent evidences have demonstrated an important role for glomerular visceral epithelial cell (podocyte) in the development and progression of diabetic nephropathy. We investigated the high-glucose (HG)-triggered signaling pathway and its role in matrix metalloproteinase (MMP) production in murine podocytes. The activity of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2), in an HG medium significantly increased during incubation of 2 to 3 days and decreased during incubation of more than 5 days revealed by Gelatin zymography. Opposite to the increases in MMP-9 activity, HG medium produced significant decreases in the protein levels of alpha5(IV) collagen. Changes in MMP-9 activity were associated with the same pattern as MMP-9 mRNA levels in podocytes exposed to HG media. HG medium rapidly activated ERK1/2 MAPK in podocytes. Moreover, ERK1/2 activation was required for HG-induced enhancement of MMP-9 activity and a decrease in the level of alpha5(IV) collagen. HG incubation rapidly induced an increase in the nuclear accumulation of Ets-1 protein. Blocking the ERK pathway suppressed HG-induced expression and nuclear accumulation of transcriptional factor Ets-1, and MMP-9 mRNA expression. We suggest that short- or long-term exposure to HG concentrations increases or decreases MMP-9 production and alpha5(IV) collagen expression in podocytes, this may contribute to the GBM abnormality caused by an imbalance in extracellular matrix (ECM) synthesis and degradation, and may play a critical role in the pathogenesis of proteinuria in diabetic nephropathy.
Division of Nephrology, Peking University First Hospital, Beijing, China.
Yaling
Y
Bai
Lizhu
L
Wang
Yongqiang
Y
Li
Senyan
S
Liu
Jingzi
J
Li
Haiyan
H
Wang
Haichang
H
Huang
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000096:biosynthesis*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D024141:Collagen Type IV; C494042:Ets1 protein, mouse; D005419:Flavonoids; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one