Low density lipoproteins and mitogenic signal transduction processes: role in the pathogenesis of renal disease.

Abstract

Abnormalities in lipid and lipoprotein metabolism are commonly observed in patients with chronic renal disease. Specifically, hyperlipidemia and the glomerular deposition of atherogenic lipoproteins (e.g., Low density lipoprotein, LDL; and its oxidized variants) are implicated in key pathobiological processes involved in the development of glomerular disease, including stimulation of monocyte infiltration into the mesangial space, mesangial cell hypercellularity, and mesangial extracellular matrix deposition. This review 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. Generally, the mitogenic intracellular signaling pathways are regulated by the activation of series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and down-stream mitogen-activated protein kinase (MAP kinase). Activated 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 cyclin/cyclin-dependent kinases play crucial role in different phases of cell growth cycle and hypercellularity of glomerular cells in various 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 hyperlipidemia, glomerular lipid deposition, and the pro-oxidative milieu within the glomerulus, through the inhibition of mitogenic signaling events, may provide protective environment against mesangial hypercellularity and subsequent matrix deposition, and the progression of renal disease.