Heparin Prevents Intracellular Hyaluronan Synthesis and Autophagy Responses in Hyperglycemic Dividing Mesangial Cells and Activates Synthesis of an Extensive Extracellular Monocyte-adhesive Hyaluronan Matrix after Completing Cell Division

Abstract

Background: Hyperglycemic dividing mesangial cells initiate intracellular hyaluronan synthesis, autophagy, and cyclin D3-mediated hyaluronan matrix formation. Results: Heparin prevents the intracellular responses but induces synthesis of a monocyte-adhesive extracellular hyaluronan matrix after cell division. Conclusion: Heparin inhibits inflammatory responses in diabetic glomeruli. Significance: Responses of dividing cells to hyperglycemia contribute to diabetic pathologies.

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

“…The latter are regarded as central to the pathogenesis of DN with glomerulosclerosis and tubulointerstitial fibrosis in the kidney (11,12). With respect to glomerulosclerosis, Hascall and co-workers (13,14) have proposed a novel paradigm suggesting hyperglycemia-induced hyaluronan synthesis that leads to autophagy and influx of monocytes causing inflammatory damage to the renal glomerulus. Such complex interrelated cellular signaling events, involving also various forms of MAP/ERK kinases and Smad proteins, have been investigated largely in glomerular cells (1-3, 15, 16), and the information concerning tubulo-interstitial cells is limited (17,18).…”

The Responses of Hyperglycemic Dividing Mesangial Cells to Heparin Are Mediated by the Non-reducing Terminal Trisaccharide

“…Previous studies demonstrated that daily intraperitoneal injection of heparin (55 mg/kg) in the diabetic rat model prevented the proteinuria and nephropathy, and sustained kidney function for 8 -10 weeks (3,4). Therefore, we determined the effects of heparin on hyperglycemic dividing rat mesangial cells (RMCs) 2 in vitro and in the diabetic rat model (2). The results showed that heparin (2.0 g/ml) prevented the intracellular hyaluronan synthesis and autophagy in vitro.…”

“…Our previous studies have shown that glomerular mesangial cells that divide in medium with glucose concentrations three times higher than normal or greater activate hyaluronan synthesis in intracellular compartments (1,2). This initiates an autophagy and subsequent extrusion of a monocyte-adhesive hyaluronan matrix after completing cell division.…”

Molecular Functions of Glycoconjugates in Autophagy

“…Current reports highlight the role that cell–matrix interactions play in regulating autophagy [132–147]. The regulatory signals emanating from the extracellular space originate from diverse binding interactions including receptor engagement by soluble ligands, as well as classic cell-matrix adhesion signaling.…”

“…Normally HAS enzyme isoforms are inactive until inserted into the plasma membrane [201, 203]. However, animal models of diabetic nephropathy and quiescent mesangial cells stimulated to grow in high glucose (25.5mM) media exhibit formation of intracellular HA chains, enhanced extracellular HA content, and marked immunohistochemical staining for LC3 [144, 147]. This intracellular HA most likely reflects activation of the organellar HAS enzyme reservoirs culminating in ER stress and autophagy induction.…”