Laboratory Investigation

Kidney International (1997) 51, 147–154; doi:10.1038/ki.1997.18

Oxidized LDL stimulates the expression of TGF-bold beta and fibronectin in human glomerular epithelial cells

Guohua Ding, Harry Van Goor, Sharon D Ricardo, Janis M Orlowski and Jonathan R Diamond

Departments of Medicine and Cellular and Molecular Physiology, The M.S. Hershey Medical Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; Department of Pathology, University Hospital Groningen, The Netherlands; Department of Medicine, Rush Medical Center, Chicago, Illinois, USA.

Correspondence: Jonathan R Diamond MD, Division of Nephrology, Department of Medicine, Hershey Medical Center, P.O. Box 850, Hershey, Pennsylvania 17033, USA.

Received 19 March 1996; Revised 28 June 1996; Accepted 29 July 1996.

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Abstract

Oxidized LDL stimulates the expression of TGF-beta and fibronectin in human glomerular epithelial cells. Abnormal lipid accumulation in glomeruli is a recognized early event in the development of glomerulosclerosis. The presence of LDL and scavenger receptors has recently been demonstrated in glomerular cells, including the visceral epithelial cells. To explore the possible molecular mechanisms of lipid-induced glomerular injury, the present investigation was conducted to examine the effects of oxidized LDL (ox-LDL) on the expression of transforming growth factor (TGF)-beta and fibronectin by cultured human glomerular epithelial cells (GEC). Cultured GEC were exposed to human ox-LDL (0 to 100 microg/ml) for various time points. Ox-LDL induced a dose- and time-dependent increase in the expression of TGF-beta mRNA. Actinomycin D, a transcriptional inhibitor, but not cycloheximide, a protein synthesis inhibitor, inhibited the response. GEC exposed to ox-LDL also demonstrated elevated levels of fibronectin mRNA. In addition, treatment of GEC with ox-LDL resulted in increased TGF-beta and fibronectin protein expression as detected by immunocytochemistry. Addition of anti-TGF-beta antibody significantly inhibited the increase in fibronectin message level induced by ox-LDL. These data suggest that ox-LDL stimulates matrix protein fibronectin in GEC by a mechanism involving expression of TGF-beta. Thus, accumulation of lipids in human glomerular epithelial cells may contribute to the pathogenesis of glomerulosclerosis through TGF-beta mediated mechanism(s).

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