High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes

Cell Physiol Biochem. 2006;17(1-2):57-68. doi: 10.1159/000091464. Epub 2006 Feb 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cells, Cultured
  • Collagen Type IV / biosynthesis*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism
  • Flavonoids / pharmacology
  • Glucose / metabolism
  • Glucose / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Matrix Metalloproteinase 9 / genetics
  • Mice
  • Podocytes / drug effects*
  • Podocytes / metabolism*
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Collagen Type IV
  • Ets1 protein, mouse
  • Flavonoids
  • Proto-Oncogene Protein c-ets-1
  • RNA, Messenger
  • Matrix Metalloproteinase 9
  • Glucose
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one