Heparin affects cytosolic glucose responses of hyperglycemic dividing mesangial cells

Mesangial expansion underlies diabetic nephropathy, leading to sclerosis and renal failure. The glycosaminoglycan heparin inhibits mesangial cell growth, but the molecular mechanism is unclear. Here, rat mesangial cells (RMCs) were growth-arrested in the G₀/G₁ phase of cell division, stimulated to divide in normal glucose (5.6 mm) or high glucose (25.6 mm) with or without heparin, and analyzed for glucose uptake. We observed that RMCs entering the G₁ phase in normal glucose with or without heparin rapidly cease glucose uptake. RMCs entering G₁ in high glucose sustained glucose uptake for the first 3 h, and high-glucose exposure of RMCs only in the first 8 h of G₁ induced the formation of an extracellular monocyte-adhesive hyaluronan matrix after cell division was completed. Moreover, a low heparin concentration under high-glucose conditions blocked glucose uptake by 1 h into G₁ Of note, glucose transporter 4 (glut4) localized on the RMC surface at G₀/G₁ and was internalized into G₁ cells under normal glucose conditions with or without heparin within 30 min. We also noted that, under high-glucose conditions, glut4 remained on the RMC surface for at least 2 h into G₁ and was internalized by 4 h without heparin and within 1 h with heparin. These results provide evidence that the influx of glucose in hyperglycemic dividing RMCs initiates intermediate glucose metabolism, leading to increased cytosolic UDP sugars, and induces abnormal intracellular hyaluronan synthesis during the S phase of cell division.