Abstract
Our previous studies showed: (i) that growth-arrested G0/G1 rat mesangial cells stimulated to divide in hyperglycemic medium initiate intracellular hyaluronan synthesis that induces autophagy and the cyclin D3-induced formation of a monocyte-adhesive extracellular hyaluronan matrix after completing cell division; and (ii) that heparin inhibits the intracellular hyaluronan and autophagy responses, but after completing division, induces hyaluronan synthesis at the plasma membrane with the formation of a larger monocyte-adhesive hyaluronan matrix. This study shows: (i) that the non-terminal trisaccharide of heparin is sufficient to initiate the same responses as intact heparin, (ii) that a fully sulfated tetrasaccharide isolated from bacterial heparin lyase 1 digests of heparin that contains a Δ-2S-iduronate on the non-reducing end does not initiate the same responses as intact heparin, and (iii) that removal of the Δ-2S-iduronate to expose the fully sulfated trisaccharide (GlcNS(6S)-IdoUA(2S)-GlcNS(6S)) does initiate the same responses as intact heparin. These results provide evidence that mammalian heparanase digestion of heparin and heparan sulfate exposes a cryptic motif on the non-reducing termini that is recognized by a receptor on dividing cells.
Highlights
Heparin prevents intracellular hyaluronan synthesis and subsequent autophagy in hyperglycemic dividing mesangial cells
This study shows: (i) that the non-terminal trisaccharide of heparin is sufficient to initiate the same responses as intact heparin, (ii) that a fully sulfated tetrasaccharide isolated from bacterial heparin lyase 1 digests of heparin that contains a ⌬-2S-iduronate on the non-reducing end does not initiate the same responses as intact heparin, and (iii) that removal of the ⌬-2Siduronate to expose the fully sulfated trisaccharide (GlcNS(6S)IdoUA(2S)-GlcNS(6S)) does initiate the same responses as intact heparin
Previous studies showed that mesangial cells in normal glucose catabolize cell surface heparan sulfate proteoglycans by an endosomal pathway that contains heparanase, which hydrolyzes the heparan sulfate chains (ϳ50 kDa) into fragments (5–10 kDa), and that a large proportion is recycled into the medium (5, 7, 24)
Summary
Heparin prevents intracellular hyaluronan synthesis and subsequent autophagy in hyperglycemic dividing mesangial cells. 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. Glomerular hyaluronan in heparintreated diabetic rats increased greatly in weeks 1–2 and declined to near control, i.e. near absence of hyaluronan, by 6 weeks, at which time the glomeruli had extensive numbers of macrophages These previous results provide evidence that dividing cells have a receptor that binds heparin and initiates the intracellular responses that inhibit activation of hyaluronan synthesis in intracellular compartments during division and that reprogram the cells to address the sustained glucose stress after division by initiating synthesis of a large monocyte-adhesive extracellular hyaluronan matrix. This study demonstrates that the motif recognized by the heparin receptor resides in the non-reducing terminal NS,6S-glucosamine trisaccharide
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