Author(s): Sohn M, Tan Y, Klein RL, Jaffa AA
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Abstract 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. CONCLUSION: 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.
This article was published in Kidney Int
and referenced in Journal of Diabetes & Metabolism