Glycation and/or oddation of LDL may promote diabetic nephropathy. The mito
gen-activated protein kinase (MAPK) cascade, which includes extracellular s
ignal-regulated protein kinases (ERKs), modulates cell function. Therefore,
we examined the effects of LDL on ERR phosphorylation in cultured rat mesa
ngial cells. In cells exposed to 100 mug/ml native LDL or LDL modified by g
lycation, and/or mild or marked (copper-mediated) oxidation, ERK activation
peaked at 5 min. Five minutes of exposure to 10-100 mug/ml native or modif
ied LDL produced a concentration-dependent (up to sevenfold) increase in ER
K activity. Also, 10 mug/ml native LDL and mildly modified LDL (glycated an
d/or mildly oxidized) produced significantly greater ERR activation than th
at induced by copper-oxidized LDL +/- glycation (P < 0.05). Pretreatment of
cells with Src kinase and MAPK kinase inhibitors blocked ERK activation by
50-80% (P < 0.05). Native and mildly modified LDL, which are recognized by
the native LDL receptor, induced a transient spike of intracellular calciu
m. Copper-oxidized (+/- glycation) LDL, recognized by the scavenger recepto
r, induced a sustained rise in intracellular calcium. The intracellular cal
cium chelator (EGTA/AM) further increased ERK activation by native and mild
ly modified LDL (P < 0.05). These findings demonstrate that native and modi
fied LDL activate ERKs 1 and 2, an early mitogenic signal, in mesangial cel
ls and provide evidence for a potential link between modified LDL and the d
evelopment of glomerular injury in diabetes.