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 [Glycobiology and Extracellular Matrices]

January 30th, 2014 by Wang, A., Ren, J., Wang, C. P., Hascall, V. C.

Growth arrested rat mesangial cells (RMCs) at a G0/G1 interphase stimulated to divide in hyperglycemic medium initiate intracellular hyaluronan synthesis that induces autophagy/cyclin D3-induced formation of a monocyte-adhesive extracellular hyaluronan matrix after completing cell division. This study shows that heparin inhibits the intracellular hyaluronan synthesis and autophagy responses, but at the end of cell division induces synthesis of a much larger extracellular monocyte-adhesive hyaluronan matrix. Heparin bound to RMC surfaces by 1 h, internalized into the golgi/ER region by 2 h, and was nearly gone by 4 h. Treatment by heparin for only the first 4 h was sufficient for its function. Streptozotocin-diabetic rats treated daily with heparin showed similar results. Glomeruli in sections of diabetic kidneys showed extensive accumulation of autophagic RMCs, increased hyaluronan matrix and influx of macrophages over 6 weeks. Hyaluronan staining in glomeruli of heparin-treated diabetic rats was very high at week 1 and decreased to near control level by 6 weeks without any RMC autophagy. However, the influx of macrophages by 6 weeks was as pronounced as in diabetic glomeruli. The results provide evidence that: 1) heparin blocks synthesis of hyaluronan in intracellular compartments, which prevents the autophagy and cyclin D3 responses thereby allowing RMCs to complete cell division and sustain function; 2) interaction of heparin with RMCs in early G1 phase is sufficient to induce signaling pathway(s) for its functions; and 3) influxed macrophages effectively remove the hyaluronan matrix without inducing pro-fibrotic responses that lead to nephropathy and proteinurea in diabetic kidneys.
  • Posted in Journal of Biological Chemistry, Publications
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