Background. Lipoprotein-X(Lp-X) is an abnormal lipoprotein found in the pla
sma of patients with familial lecithin:cholesterol acyltransferase (LCAT) d
eficiency. The majority of patients with this disorder develop progressive
glomerulosclerosis. One key event in the pathogenesis of glomerulosclerosis
is the infiltration of monocytes into affected glomeruli. Mesangial cells
can synthesize and secrete monocyte chemoattractant protein-1 (MCP-1), an i
mportant chemoattractant for monocytes. The objective of the present study
was to examine the effect of Lp-X on MCP-1 expression in mesangial cells le
ading to an enhanced monocyte chemotaxis and to elucidate the mechanisms in
volved in this process.
Methods. Lp-X was isolated from the plasma of a patient with familial LCAT
deficiency. After rat mesangial cells were incubated with Lp-X for four or
six hours, the expression of MCP-1 mRNA was determined by nuclease protecti
on assay, and MCP-1 protein was measured by Western immunoblotting analysis
. Monocyte chemotaxis was determined by using a Micro Chemotaxis Chamber.
Results. Lp-X (50 to 100 nmol/ml) stimulated mesangial cell MCP-1 mRNA expr
ession (137 to 220%) and MCP-1 protein levels (233 to 375%). Conditioned me
dia collected from Lp-X-treated mesangial cells stimulated human acute mono
cytic leukemia (THP-I) monocyte chemotaxis (165 to 200%). The increase in M
CP-1 expression in mesangial cells was associated with an elevation of intr
acellular diacylglycerol levels, and activation of protein kinase C (PKC) a
s well as nuclear factor-KS (NF-kappaB).
Conclusion. These results suggest that Lp-X participates in the pathogenesi
s of glomerulosclerosis and subsequent renal failure in familial LCAT defic
ient patients by stimulating monocyte infiltration via a mechanism involvin
g mesangial MCP-1 expression.