Interactions of LDL and modified LDL with mesangial cells and matrix.
Hyperlipidemia may play a role in the progression of diabetic and other renal diseases. Low density lipoprotein (LDL) and other proteins including extracellular matrix components undergo nonenzymatic glycation in vivo. We examined the effects of glycation of LDL as occurs in diabetes (4 to 8%) on binding and uptake by mesangial cells and their proliferation. The glycation of LDL (g-LDL) significantly decreased its binding and uptake by mesangial cells by 15 to 20%, indicating that glycated LDL binds to the LDL receptor, but with lower affinity than LDL. Both LDL and g-LDL modestly stimulated [3H] thymidine incorporation into mesangial cells at 5 to 10 micrograms/ml. Native, oxidized (Ox-LDL) and glycated LDL all bound to the extracellular matrix generated by rat mesangial cells in culture. The binding of LDL, Ox-LDL and g-LDL to mesangial matrix was two to four times higher than to mesangial cells. Binding of LDL and g-LDL was significantly higher to glycolaldehyde modified matrix, which serves as an in vitro model for nonenzymatic glycation end-product cross-linking of matrix which occurs in long-standing diabetes. Based on these findings, we propose that glycation of LDL decreases its binding and uptake by the LDL receptor of mesangial cells and may slow its catabolism. Furthermore, LDL bound to extracellular mesangial matrix can undergo oxidation and generate cytotoxic LDL components. This process may be further enhanced by advanced glycation of the mesangial matrix in diabetes, contributing to glomerular pathology.
Gupta
S
S
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.
Rifici
V
V
Crowley
S
S
Brownlee
M
M
Shan
Z
Z
Schlondorff
D
D
D000818:Animals; D002455:Cell Division; D005109:Extracellular Matrix / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D000093844:Glycated Proteins
D005947:Glucose; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins