Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy

Biochem J. 2001 Oct 1;359(Pt 1):77-87. doi: 10.1042/0264-6021:3590077.


We characterized a rabbit polyclonal antibody raised against human recombinant connective tissue growth factor (CTGF). The antibody recognised a higher molecular mass form (approx. 56 kDa) of CTGF in mesangial cell lysates as well as the monomeric (36-38 kDa) and lower molecular mass forms (<30 kDa) reported previously. Immunohistochemistry detected CTGF protein in glomeruli of kidneys of non-obese diabetic mice 14 days after the onset of diabetes, and this was prominent by 70 days. CTGF protein is also present in glomeruli of human patients with diabetic nephropathy. No CTGF was detected in either normal murine or human glomeruli. Transient transfection of a transformed human mesangial cell line with a CTGF-V5 epitope fusion protein markedly increased fibronectin and plasminogen activator inhibitor-1 synthesis in cultures maintained in normal glucose (4 mM) conditions; a CTGF-antisense construct reduced the elevated synthesis of these proteins in high glucose (30 mM) cultures. Culture of primary human mesangial cells for 14 days in high glucose, or in low glucose supplemented with recombinant CTGF or transforming growth factor beta1, markedly increased CTGF mRNA levels and fibronectin synthesis. However, whilst co-culture with a CTGF-antisense oligonucleotide reduced the CTGF mRNA pool by greater than 90% in high glucose, it only partially reduced fibronectin mRNA levels and synthesis. A chick anti-CTGF neutralizing antibody had a similar effect on fibronectin synthesis. Thus both CTGF and CTGF-independent pathways mediate increased fibronectin synthesis in high glucose. Nevertheless CTGF expression in diabetic kidneys is likely to be a key event in the development of glomerulosclerosis by affecting both matrix synthesis and, potentially through plasminogen activator inhibitor-1, its turnover.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy
  • Blotting, Western
  • Cells, Cultured
  • Cloning, Molecular
  • Connective Tissue Growth Factor
  • DNA, Complementary
  • Diabetes Mellitus, Experimental / etiology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Fibronectins / metabolism
  • Gene Expression Regulation / drug effects
  • Glomerular Mesangium / metabolism
  • Glomerular Mesangium / pathology
  • Glucose / metabolism
  • Glucose / pharmacology
  • Humans
  • Immediate-Early Proteins / physiology*
  • Immunoenzyme Techniques
  • Immunoglobulin G / pharmacology
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Kidney / metabolism
  • Mice
  • Mice, Inbred NOD
  • Oligonucleotides, Antisense / pharmacology
  • Plasminogen Activator Inhibitor 1 / metabolism
  • RNA, Messenger
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1


  • CCN2 protein, human
  • CCN2 protein, mouse
  • DNA, Complementary
  • Fibronectins
  • Immediate-Early Proteins
  • Immunoglobulin G
  • Intercellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Glucose