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Am J Physiol Renal Physiol 277: F369-F376, 1999;
0363-6127/99 $5.00
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Vol. 277, Issue 3, F369-F376, September 1999

LDL stimulates collagen mRNA synthesis in mesangial cells through induction of PKC and TGF-beta expression

Hyun Soon Lee, Bong Cho Kim, Hye Kyung Hong, and Young Sook Kim

Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea

Abnormal lipid accumulation in glomeruli could be implicated in the pathogenesis of glomerulosclerosis. Low-density lipoprotein (LDL) stimulates collagen mRNA expression in cultured human mesangial cells (HMC). To explore the possible molecular mechanisms by which LDL promotes collagen gene expression, we examined the effects of LDL on protein kinase C (PKC) activity and transforming growth factor-beta (TGF-beta ) expression in relation to collagen gene regulation in HMC. LDL (200 µg/ml) induced an acute increase in PKC activity, particularly PKC-alpha and -delta , within 15 min, which decreased to control value at 2 h. LDL stimulated TGF-beta 1, and alpha 1(I) and alpha 1(IV) collagen mRNA expression within 30 min of incubation with HMC, and levels remained elevated until hour 4. LDL induced the secretion of TGF-beta by HMC. This TGF-beta was shown by CCL-64 mink lung cell assay to be, in part, bioactive. The stimulatory effects of LDL on collagen gene regulation in HMC were blocked by the inhibition of PKC using GF-109203X (GFX) or the downregulation of PKC using phorbol myristate acetate. Neutralizing antibody to TGF-beta inhibited the increased collagen mRNA expression by HMC exposed to LDL. The downregulation or inhibition of PKC did not affect the stimulatory effect of LDL on TGF-beta mRNA or protein expression. These results suggest that in HMC, LDL stimulates collagen mRNA expression through the rapid activation of PKC-alpha and -delta and transcriptional upregulation of TGF-beta . Thus PKC and TGF-beta may function as independent key signaling intermediaries in the pathway by which LDL upregulates collagen gene expression in HMC.

glomerulosclerosis; lipids; transmembrane signaling; collagen gene


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