High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-ϰB-dependent

Abstract

AbstractsAims/hypothesis. Infiltration of mononuclear cells and glomerular enlargement accompanied by glomerular cell proliferation are very early characteristics of the pathophysiology of diabetes. To clarify the mechanism of early diabetic nephropathy, we measured [ 3 H]-thymidine incorporation and cell numbers to show the influence of a high ambient glucose concentration and the osmotic effect on rat mesangial cell proliferation. We also measured the effect of high glucose on the expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1 by flow cytometry and semiquantitative RT-PCR in mesangial cells and the adhesion of leukocytes to mesangial cells. Methods/results. Cells exposed to high d-glucose (30 mmol/l) caused an increase in [ 3 H]-thymidine incorporation and cell numbers at 24 and 48 h and normalized at 72 h (p < 0.05), whereas these changes were not found in high mannitol (30 mmol/l), IL-1b, or TNFa-stimulated mesangial cells. Cells exposed to high-glucose (15, 30, or 60 mmol/l) or osmotic agents (l-glucose, raffinose and mannitol) showed that intercellular adhesion molecule-1 expression began to increase after 24 h, reached its maximum at 24 and 48 h and gradually decreased afterwards. The stimulatory effects of high glucose and high mannitol on mRNA expression were observed as early as 6 h and reached its maximum at 12 h. Up-regulation of ICAM-1 protein and mRNA was also found in IL-1-b and TNF-a-stimulated mesangial cells. Neither vascular adhesion molecule-1 protein nor mRNA expression was, however, affected by high glucose and high mannitol. Notably, the protein kinase C inhibitors calphostin C and staurosporine reduced high glucose-or high mannitol-induced intercellular adhesion molecule-1 mRNA expression and high glucose-induced proliferation. Furthermore, the NF-kB inhibitor N-tosyl-l-phenylalanine chloromethyl ketone reduced high glucose-or high mannitol-induced intercellular adhesion molecule-1 mRNA expression and high glucose-induced proliferation. Results showed that high glucose (15, 30 mmol/l) or high concentrations of osmotic agents remarkably increased the number of adherent leukocytes to mesangial cells (p < 0.01) compared with control cells (5 mmol/l dglucose). Functional blocking of intercellular adhesion molecule-1 on mesangial cells with rat intercellular adhesion molecule-1 monoclonal antibody, calphostin C, staurosporine, or N-tosyl-l-phenylalanine chloromethyl ketone significantly inhibited high glucose-or high mannitol-induced increase in leukocyte adhesion (p < < 0.05). Conclusion/interpretation. These results suggest that high glucose can upregulate intercellular adhesion molecule-1 protein and mRNA expression but not vascular adhesion molecule-1 expression in mesangial cells and promote leukocyte adhesion through

TGF-β1-induced PINCH-1-ILK-α-parvin complex formation regulates mesangial cell proliferation and hypertrophy

“…The previous studies have shown that TGF-β1 results in transient proliferation of rats GMCs, followed by growth inhibition (Park et al, 2000;Drummond and Mauer, 2002), and similar results were also observed in our previous study (Rho et al, 2004). In contrast, TGF-β1 inhibits the proliferation of human and mouse GMCs which were cultured under serumfree condition (Stephenson et al, 1998).…”

Intercellular Adhesion Molecule-1–Deficient Mice Are Resistant Against Renal Injury After Induction of Diabetes

“…5) Oxidative stress has been documented to increase ICAM-1 expression (30). 6) Osmotic agents upregulate ICAM-1 expression in rat mesangial cells (31) and in human umbilical vein endothelial cells (32). Our results showed that the infiltration of macrophages into the glomeruli was lower in diabetic ICAM-1 Ϫ/Ϫ mice compared with diabetic ICAM-1 ϩ/ϩ mice (reduction rate 78.5%), suggesting that ICAM-1 is a critical molecule for the infiltration of macrophages into glomeruli in diabetic nephropathy.…”

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

“…Here, the authors found that betaine (trimethylglycine), a natural specific type of zwitterion, known to improve visual acuity, has antioxidant properties and inhibits pathological neovascularization of human retinal microvascular endothelial cells exposed to high glucose levels, by attenuating ROS production, and subsequently suppressing both the VEGF receptor (VEGFR)-2 signaling pathway and VEGF production [3]. Betaine was, here, reported to act on the hyperosmolar component of hyperglycemia [4], a biophysical mechanism known to contribute to the development of microvascular disease in diabetes [5][6][7]. Thus, betaine would act on one pathway leading from hyperglycemia to microangiopathy.…”