Heparin interaction with a receptor on hyperglycemic dividing cells prevents intracellular hyaluronan synthesis and autophagy responses in models of type 1 diabetes

Abstract

Previous studies and ongoing research indicate the importance of an interaction between a putative receptor on dividing cells in hyperglycemia and the non-reducing end motifs of heparin stored in mast cell secretory granules and how this interaction prevents activation of hyaluronan synthesis in intracellular compartments and subsequent autophagy. This suggests a new role for endosomal heparanase in exposing this cryptic motif present in the initial large heparin chains on serglycin and in the highly sulfated (NS) domains of heparan sulfate.

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

“…During or after entry into the secretory granules, the chains are hydrolyzed by heparanase to 10 -15 kDa (18,19). There is only one heparanase in the human genome, and it hydrolyzes bonds between hexuronate residues and GlcNS(6S) (20).…”

Opposing Functions of Heparanase-1 and Heparanase-2 in Cancer Progression

“…Yet, non-tumor (host) cells including T lymphocytes, B lymphocytes, neutrophils, monocyte/ macrophages (see Glossary), endothelial cells, osteoclasts and fibroblasts can also upregulate heparanase expression upon activation and thereby contribute not only to cancer progression and chemoresistance [5, 12, 30–34], but also to acute and chronic inflammation [35–37], autoimmunity [36, 38], atherosclerosis [39], tissue fibrosis [40], kidney dysfunction [41–44], ocular surface dysfunction [45], viral infection [46], diabetes [47] and diabetic complications [48, 49]. These functions dynamically impact multiple pathological pathways, but at the same time, may fulfill some normal functions associated, for example, with vesicular traffic, exosome formation, lysosomal-based secretion, stress response, and heparan sulfate turnover [50–52]. Noteworthy, heparanase appears to activate cells of the innate immune system and soluble HS fragments generated by heparanase trigger the expression and secretion of pro-inflammatory cytokines through toll-like receptors (TLR) [1, 53–55].…”