<Originals>Response of cultured mesangial cells to native and oxidized low-density lipoproteins in rat diabetic nephropathy
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To elucidate the role of low-density lipoprotein (LDL) on the progression of diabetic glomerulopathy, we studied the response to native (n-) and oxidized (ox-) LDL on cultured mesangial cells (MC) from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes mellitus. Immunofluorescent staining using anti-LDL antibody revealed that glomerular LDL deposition increased with the age of the rats, paralleling the morphological progression of glomerulopathy. MC from OLETF rats, with two different stages of the disease, were isolated and cultured ; i.e. young (10-15-week-old) OLETF rats (y-OLETF) prior to the manifestation of nephropathy and old (55-65-week-old) OLETF rats (o-OLETF) showing well-developed diabetic nephropathy. MC were also prepared from control rats (The Long-Evans Tokushima Otsuka : LETO rats). The addition of a low dose of n-LDL (10μg/ml) to the culture media significantly stimulated DNA synthesis of y-OLETF MC compared with o-OLETF MC and LETO MC (p<0.05). A high dose of n-LDL (100μg/ml) exhibited cytotoxic effects on these cells. Exposure to ox-LDL minimally affected DNA synthesis of OLETF or LETO MC. To reveal LDL receptor types, fluorescence-labeled (Dil-) LDL or ^<125>I-labeled LDL was applied to MC. Cellular uptake of Dil-n-LDL and the binding to ^<125>I-n-LDL were prominent in y-OLETF MC, but not in those of o-OLETF or LETO. The incorporation of Dil-acetylated-LDL and binding to ^<125>I-ox-LDL were evident in o-OLETF MC. After stimulation with n-LDL or ox-LDL, type I and type III collagen expression, along with transforming growth factor (TGF)-β expression were prominent in o-OLETF, compared with those of y-OLETF or LETO, while matrix metalloprotease-2 expression in MC was similar among o-OLETF, y-OLETF and LETO. These findings indicated that n-LDL is mitogenic for y-OLETF MC, which expressed high levels of LDL-receptors rather than scavenger-receptors. ox-LDL stimulates o-OLETF MC, which possesses predominantly scavenger receptors, to synthesize extracellular matrix. n-LDL and ox-LDL stimulated OLETF MC to proliferate during the early stage and to produce extracellular matrix during the late stage, respectively, thus contributing to the progression of diabetic glomerulopathy.
- 近畿大学の論文
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