Atherogenic lipoproteins and tyrosine kinase mitogenic signaling in mesangial cells

Abstract

Mesangial hypercellularity is a critical early histopathological finding seen in human and experimental glomerular diseases. Hyperlipidemia and the glomerular deposition of atherogenic lipoproteins [for example, low-density lipoprotein (LDL) and its oxidized variants, minimally oxidized/modified LDL (mm-LDL)] are commonly associated with mesangial hypercellularity and the development of glomerular disease. This article reviews signal transduction pathways involved in cell proliferation and provides evidence for the participation of atherogenic lipoproteins in intracellular signaling pathways for mesangial cell proliferation. The mitogenic intracellular signaling pathways are regulated by the activation of a series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and downstream mitogen-activated protein (MAP) kinase. Activated MAP kinase, through translocating into the nucleus and the activation of various transcription factors and proto-oncogenes, regulates cellular proliferation. Murine mesangial cells were stimulated with LDL and mm-LDL and were analyzed for the tyrosine kinase activity, phosphorylation of membrane proteins, activation of Ras and MAP kinase, and cell proliferation. The results indicated that the stimulation of mesangial cells with LDL and, with greater activity, mm-LDL induced the phosphorylation of membrane platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors, activated Ras, and resulted in sustained (up to 24 hr) activation of MAP kinase. LDL/mm-LDL-mediated mesangial cell proliferation and MAP kinase activation were dependent on the activation of tyrosine kinases. We suggest that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the activation of membrane receptor tyrosine kinases, activate the Ras and MAP kinase signaling cascade leading to DNA synthesis and subsequent cell proliferation.