Details

Autor(en) / Beteiligte

• Westwood, M E

Titel

Receptor-mediated endocytosis of serum albumins modified by methylglyoxal and glucose-derived advanced glycation endproducts

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

1996

Link zum Volltext

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The non-enzymatic reaction of proteins with glucose to form advanced glycation end-products (AGE), and with methylglyoxal to form AGE-like compounds, has been linked to the development of diabetic complications (retinopathy, neuropathy, nephropathy). AGE- and methylglyoxal-modified proteins bound cell surface receptors on murine P388D$\sb1$ macrophages and human THP-1 monocytic cells in vitro. Bovine serum albumin highly modified with methylglyoxal (MG-BSA$\sb{24}$; 23 lysine & 21 arginine residues modified) bound cell surface receptors on P388D$\sb1$ cells with a K$\rm\sb{D}$ value of $421\pm92$ nM and there were $6.1\pm0.6\times10\sp5$ receptors per cell. Bovine serum albumin modified with AGE (AGE-BSA; 40 lysine & 14 arginine residues modified) bound cell surface receptors on P388D$\sb1$ cells with a K$\rm\sb{D}$ value of $343\pm27$ nM and there were $5.9\pm0.1\times10\sp5$ receptors per cell. Human serum albumin modified with 2-3 methylglyoxal moieties per molecule (MG-HSA$\sb{\min})$ bound cell surface receptors on THP-1 cells with a K$\rm\sb{D}$ value of $377\pm34$ nM and there were $5.9\pm0.3\times10\sp5$ receptors per cell. Glucose-derived AGE-modified human serum albumin (AGE-HSA; 21 lysine & 16 arginine residues modified) bound cell surface receptors on THP-1 cells with a K$\rm\sb{D}$ value of $535\pm61$ nM and there were $1.31\pm0.56\times10\sp6$ receptors per cell. At 37$\sp\circ$C, receptor binding of MG-BSA$\sb{24}$ and AGE-BSA by P388D$\sb1$ cells and MG-HSA$\sb{\min}$ and AGE-HSA by THP-1 cells was followed by endocytosis and lysosomal degradation of the modified protein. MG-HSA$\sb{\min}$ and AGE-HSA induced functional responses in THP-1 cells: growth stimulation mediated by the expression of macrophage colony stimulating factor (CSF-1) and production and secretion of interleukin-$1\beta$ (IL-$1\beta).$ MG-HSA$\sb{\min}$ and AGE-HSA induced cell growth with equal potency. MG-HSA$\sb{\min}$ was a more potent inductor of IL-$1\beta$ expression than AGE-HSA. The receptor-mediated endocytosis and functional effects induced by MG-HSA$\sb{\min}$ suggest that proteins minimally-modified by methylglyoxal may be particularly important ligands for monocyte and macrophage receptors linked to monocyte proliferation and induction of cytokine synthesis. These proliferative and pro-inflammatory responses in vivo may contribute to the development of diabetic complications.