Low density lipoproteins transactivate EGF receptor: role in mesangial cell proliferation

Hyperlipidemia and the glomerular accumulation of atherogenic lipoproteins (low density lipoprotein, LDL; and its oxidatively-modified variants, ox-LDL) are commonly associated with the development of glomerular mesangial proliferative diseases. However, cellular signaling mechanisms by which atherogenic lipoproteins stimulate mesangial cell proliferation are poorly defined. In this study, we examined the effect of atherogenic lipoproteins on the activation of mesangial cell epidermal growth factor (EGF) receptor, mitogen activated protein kinase (MAP kinase), Ras, and mesangial cell proliferation. Stimulation of mesangial cells with LDL, and with greater activity, ox-LDL, markedly induced the transactivation of EGF receptor within 5 min of stimulation; the effect persisted up to at least 60 min LDL, and with a greater degree, ox-LDL, increased the activation of Ras, MAP kinase, and mesangial cell proliferation. Inhibition of EGF receptor kinase activity and/or MAP kinase activation blocked both LDL- and ox-LDL-induced mesangial cell proliferation. We suggest that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the transactivation of EGF receptor, stimulate down-stream Ras-MAP kinase signaling cascade leading to mesangial cell proliferation. Regulation of glomerular accumulation of atherogenic lipoproteins and/or EGF receptor signaling may provide protective environment against mesangial hypercellularity seen in glomerular diseases.