Glycation and/or oxidation of LDL may promote diabetic nephropathy. The mitogen-activated protein kinase (MAPK) cascade, which includes extracellular signal-regulated protein kinases (ERKs), modulates cell function. Therefore, we examined the effects of LDL on ERK phosphorylation in cultured rat mesangial cells. In cells exposed to 100 µg/ml native LDL or LDL modified by glycation, and/or mild or marked (copper-mediated) oxidation, ERK activation peaked at 5 min. Five minutes of exposure to 10-100 µg/ml native or modified LDL produced a concentration-dependent (up to sevenfold) increase in ERK activity. Also, 10 µg/ml native LDL and mildly modified LDL (glycated and/or mildly oxidized) produced significantly greater ERK activation than that induced by copper-oxidized LDL ± glycation (P < 0. D iabetes is the most common cause of end-stage renal disease in the Western world (1). Features of diabetic nephropathy include an alteration in glomerular cellularity, with early hypercellularity and late hypocellularity, thickened basement membranes, and increased mesangial matrix (2). Associations between elevated cholesterol levels, atherosclerosis, and the progression of renal damage are recognized (3-7). There is an extensive amount of literature suggesting that qualitative as well as quantitative abnormalities of the major cholesterol carrier LDL may contribute to its atherogenicity (7-11). More recently, LDL has been implicated in diabetic microvascular complications (12,13). Qualitative abnormalities of LDL occurring in diabetes include enhanced glycation (9,14), oxidation (14,15), and glycoxidation (combined glycation and oxidation) (9,11).Modified lipoproteins may be involved in nephrosclerosis and glomerulosclerosis (15)(16)(17)(18)(19)(20)(21)(22)(23). Oxidized LDL has been demonstrated in renal glomeruli in vivo, and intravenous administration of in vitro-oxidized LDL results in renal injury and LDL accumulation (23). Diabetic nephropathy-like lesions have also been induced in a rat model by glycated and glycoxidized albumin (24-26). With use of cultured mesangial cells, cytotoxicity (23,27) and enhanced production of mesangial matrix (23) in response to LDL have been demonstrated. We previously demonstrated that a noncytotoxic dose of glycated LDL increases transforming growth factor (TGF)-␤ mRNA expression (28): TGF-␤ is a modulator of mesangial cell survival and matrix production (29,30).Mitogen-activated protein kinases (MAPKs) are serine threonine-specific kinases that are activated in response to extracellular stimuli by dual phosphorylation at conserved tyrosine and threonine residues. Activation of the MAPK signaling pathways has been associated with effects relevant to vascular pathology in cultured cells implicated in macrovascular disease (31-33) and, more recently, in renal disease (34-36). Effects include stimulation or inhibition of cell proliferation (34,35), induction of apoptosis (37), and matrix production (36). There are at least three parallel series of MAPK cascades: 1) p38 MAPK; 2) stress-...

In budding yeast, the spindle position checkpoint ensures that cells exit from mitosis only when their spindle is properly aligned along the mother–bud axis. Exit from mitosis is controlled by both negative signals in the mother cell compartment and positive signals in the bud.