Evidence for low-density lipoprotein-induced expression of connective tissue growth factor in mesangial cells.
BACKGROUND
Although hyperlipidemia is a risk factor for the progression of renal damage, the relationship between increased plasma lipoproteins and glomerular injury is poorly defined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases and its expression is up-regulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDLs) promote glomerular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen I.


METHODS
The effects of LDL on CTGF and collagen I expression were carried out in rat mesangial cells.


RESULTS
Treatment of mesangial cells with LDL for 24 hours produced a significant increase in the protein levels of CTGF and collagen I compared to unstimulated controls. To explore if CTGF and collagen I are downstream targets for regulation by transforming growth factor-beta (TGF-beta), mesangial cells were treated with various concentration of TGF-beta for 24 hours. TGF-beta produced a concentration-dependent increase in the protein levels of CTGF and collagen I. The increase in CTGF and collagen I induced by LDL was significantly inhibited by neutralizing anti-TGF-beta antibodies. Inhibition of p38(mapk) or p42/44(mapk) activities did not affect LDL-induced TGF-beta1, CTGF, and collagen I expression, whereas inhibition of c-Jun NH2-terminal kinase (JNK) suppressed LDL-induced TGF-beta, CTGF, and collagen I expression.


CONCLUSIONS
These findings implicate JNK pathway and TGF-beta1 as key players in LDL signaling leading to CTGF and collagen I expression in mesangial cells. The data also point to a potential mechanistic pathway through which lipoproteins may promote glomerular injury.
Sohn
Mimi
M
Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Tan
Yan
Y
Klein
Richard L
RL
Jaffa
Ayad A
AA
D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor; D005920:Glomerular Mesangium / Q000187:drug effects / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1
C526316:CCN2 protein, rat; D024042:Collagen Type I; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor