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
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
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肝素可防止高血糖分裂系膜细胞的细胞内透明质酸合成和自噬反应，并在完成细胞分裂后激活广泛的细胞外单核细胞粘附透明质酸基质的合成
DOI：
10.1074/jbc.m113.541441
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发表时间：
2014-03-28
影响因子：
4.8
通讯作者：
Hascall, Vincent C.
中科院分区：
文献类型：
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作者：
Wang, Aimin;Ren, Juan;Hascall, Vincent C.
背景：高血糖分裂的系膜细胞启动细胞内透明质酸合成、自噬和细胞周期蛋白D3介导的透明质酸基质形成。结果：肝素可阻止细胞内反应，但可诱导细胞分裂后单核细胞黏附细胞外透明质酸基质的合成。结论：肝素可抑制糖尿病肾小球的炎症反应。意义：分裂细胞对高血糖的反应有助于糖尿病的发病。生长停滞的大鼠肾小球系膜细胞(RMC)在高血糖介质中被刺激分裂到G(0)/G(1)间期时，启动细胞内透明质酸合成，诱导自噬/细胞周期蛋白D3诱导单核细胞黏附的细胞外透明质酸基质的形成。这项研究表明，肝素抑制细胞内透明质酸合成和自噬反应，但在细胞分裂结束时，它诱导合成更大的细胞外单核细胞粘附性透明质酸基质。肝素与RMC表面结合1 h，2 h内化进入高尔基体/内质网区，4 h基本消失，肝素仅处理前4 h即可发挥作用。每天用肝素治疗的链脲佐菌素糖尿病大鼠也有类似的结果。糖尿病肾脏切片中的肾小球显示自噬RMCs广泛聚集，透明质酸基质增多，6周后巨噬细胞大量涌入。肝素处理的糖尿病大鼠肾小球透明质酸染色在1周时很高，6周时降至接近对照水平，未见任何RMC自噬。然而，6周时巨噬细胞的流入与糖尿病肾小球一样明显。结果如下：1)肝素阻断细胞内透明质酸的合成，阻止自噬和细胞周期蛋白D3的反应，从而使RMC完成细胞分裂和维持功能；2)肝素在G(1)期与RMC的相互作用足以诱导其功能的信号通路(S)；3)流入的巨噬细胞有效地清除透明质酸基质，而不会引发导致糖尿病肾脏病变和蛋白尿素的促纤维化反应。
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.Growth-arrested rat mesangial cells (RMCs) at a G(0)/G(1) 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 it induces synthesis of a much larger extracellular monocyte-adhesive hyaluronan matrix. Heparin bound to RMC surfaces by 1 h, internalizes into the Golgi/endoplasmic reticulum 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 the 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 are as follows: 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 G(1) 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.