Lipoprotein-stimulated mesangial cell proliferation and gene expression are regulated by lipoprotein lipase.
BACKGROUND
Hyperlipidemia accelerates the progression of glomerular disease, and lipoproteins bind glomerular mesangial cells (MC) and induce proliferation and cytokine expression. In the vessel wall, the binding of lipoproteins to endothelial cells is markedly enhanced by lipoprotein lipase (LpL), synthesized by the underlying smooth muscle cells. While it is known that LpL is localized to the glomerulus, it is not known if and how it modulates the lipoprotein-mesangial interaction.


METHODS
Very low-density lipoprotein (VLDL) was isolated from rats and was used to treat cultured primary rat MCs. Binding studies were done with and without LpL and with/without pretreatment with heparanase, which degrades cell surface heparan sulfate proteoglycan (HSPG), known to modulate the LpL-lipoprotein interaction in blood vessels. VLDL/LpL was also used to assess MC proliferation and gene expression of the cytokine platelet-derived growth factor (PDGF).


RESULTS
LpL enhanced VLDL binding to MCs by as much as 200-fold, and most of this effect was blocked by pretreatment with heparanase. LpL amplified VLDL-driven MC proliferation and increased VLDL-induced PDGF expression. Heparanase pretreatment of cells eliminated both of these amplifications. LpL alone increased MC proliferation and PDGF gene expression.


CONCLUSIONS
As in the vessel wall, LpL enhances VLDL binding to MCs. MCs respond to LpL binding by proliferating and expressing cytokines such as PDGF. LpL may be a crucial paracrine mediator of the glomerular response to circulating lipoproteins, amplifying a response that includes cytokine elaboration, influx of circulating monocytes, and eventual sclerosis.
Stevenson
F T
FT
Department of Medicine, University of California, Davis, California 95616, USA. ftstevenson@ucdavis.edu
Shearer
G C
GC
Atkinson
D N
DN
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D005921:Glomerulonephritis / Q000378:metabolism / Q000503:physiopathology; D005966:Glucuronidase / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D019899:Paracrine Communication / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D000099175:Heparanase
D005966:Glucuronidase; D006497:Heparan Sulfate; D008071:Lipoprotein Lipase; D008079:Lipoproteins, VLDL; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D000099175:Heparanase; C075278:platelet-derived growth factor A