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J. Biol. Chem., Vol. 276, Issue 52, 49142-49147, December 28, 2001
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,
,
, and
**
From the Mesangial expansion is a key feature
in the pathogenesis of numerous renal diseases involving the
glomerulus. Studies indicate that mutations in apolipoprotein E (apoE)
might independently contribute to kidney dysfunction. Although the role
of apoE as an atheroprotective molecule is well established, its role
in kidney is unclear. In this study, we sought to explore whether apoE
has a protective function in kidney. Northern blotting and reverse
transcriptase-polymerase chain reaction showed apoE expression in
kidney, and mesangial cell is a major source of apoE in kidney. In the
kidneys of 14-16-month-old apoE-null mice, hematoxylin-eosin (HE)
staining revealed increased mesangial cell proliferation and matrix
formation compared with wild type mice or apoB-overexpressing mice,
which have elevated plasma cholesterol and triglycerides. These data
suggest that lack of apoE, rather than hyperlipidemia, contributes to
increased mesangial expansion. We isolated mesangial cells from mouse
kidney and determined the effect of apoE on cell growth. ApoE (E3, 10 µg/ml) completely inhibited serum, platelet-derived growth factor (10 ng/ml), as well as low density lipoprotein-induced mesangial cell
proliferation. Among the three isoforms, E3 was found to be most
effective in inhibiting mesangial cell proliferation. ApoE did not show
any cytotoxic effect, and moreover, inhibited mesangial cell apoptosis
induced by oxidized low density lipoprotein. These data suggest that
apoE regulates growth as well as survival of mesangial cells. We
previously showed that apoE induces matrix heparan sulfate proteoglycan
(HSPG) in vascular cells, which has an antiproliferative effect.
Similarly, apoE induced the mesangial matrix HSPG. Perlecan is the
major HSPG of mesangial matrix and subendothelial space, and consistent
with this, blockade of perlecan reversed the antiproliferative effect
of apoE. Immunohistochemistry revealed reduced staining of
perlecan in kidney from apoE-null mice. Because the loss of anionic
HSPG in the basement membrane and mesangial matrix is associated with
disruption of filtration barrier, these data suggest a novel role for
kidney apoE in preserving the filtration barrier. In summary, apoE has
a protective function in kidney as an autocrine regulator of
mesangial expansion and kidney function.
Department of Radiation Oncology
and ¶ Medicine, North Shore-Long Island Jewish Health System,
Manhasset, New York 11030, the § Division of Preventive
Medicine, Department of Medicine, Columbia University, New York,
New York 10032, and the
Reddy US Therapeutics,
Norcross, Georgia 30071
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