Publication: Low density lipoproteins and mitogenic signal transduction processes:
Role in the pathogenesis of renal disease
Authors
Kamanna, V.S.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Abnormalities in lipid and lipoprotein
metabolism are commonly observed in patients with
chronic renal disease. Specifi c a l l y, hyperlipidemia and
the glomerular deposition of atherogenic lipoproteins
(e.g., Low density lipoprotein, LDL; and its oxidized
variants) are implicated in key pathobiological processes
i nvo l ved in the development of glomerular disease,
including stimulation of monocyte infiltration into the
mesangial space, mesangial cell hy p e r c e l l u l a r i t y, and
mesangial extracellular matrix deposition. This rev i ew
discusses recent understanding of glomerular mitogenic
responses, intracellular signaling events associated with
mesangial hypercellularity in renal diseases, and the
participation of cholesterol and atherogenic lipoproteins
in intracellular signaling pathways involved in mesangial
cell proliferation.
G e n e r a l l y, the mitogenic intracellular signaling
p a t h ways are regulated by the activation of series of
transmembrane and cytoplasmic protein tyrosine kinases
that converge into the activation of Ras and down-stream
m i t o g e n - a c t ivated protein kinase (MAP kinase).
A c t ivated MAP kinase, through translocating into the
nucleus and the activation of various transcription factors
and protooncogenes, regulate cell proliferation. The
importance of mitogenic intracellular signaling in
mesangial proliferative disease has only recently been
recognized and showed that the activation of MAP kinase and/or cy c l i n / cyclin-dependent kinases play
crucial role in different phases of cell growth cycle and
hypercellularity of glomerular cells in va r i o u s
experimental renal diseases. Using glomerular mesangial
cells as an in-vitro model system, studies from our
laboratory indicated that the accumulation of LDL and
more potently its oxidized forms within the glomerulus,
through the activation of membrane receptor tyrosine
kinases (e.g., EGF receptor), activate Ras and MAP kinase signaling cascade leading to DNA synthesis and
subsequent mesangial cell proliferation.
These data suggest that atherogenic lipoproteins may
act as one of the major endogenous modulators for
mitogenic signaling response and cell proliferation
within the glomerulus. It is reasonable to speculate that
the correction or reduction of hy p e r l i p i d e m i a ,
glomerular lipid deposition, and the pro-oxidative milieu
within the glomerulus, through the inhibition of
mitogenic signaling events, may provide protective
e nvironment against mesangial hypercellularity and
subsequent matrix deposition, and the progression of
renal disease.
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