Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes
Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes
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DOI：
10.2337/db15-1662
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发表时间：
2016-09-01
期刊：
影响因子：
7.7
通讯作者：
Flamion, Bruno
中科院分区：
文献类型：
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作者：
Dogne, Sophie;Rath, Geraldine;Flamion, Bruno
透明质酸（HA）是参与血管壁和内皮肾小球通透性屏障的糖萼的主要成分。已知内吞透明质酸酶HYAL1可在不同类型的细胞（包括内皮细胞）中将透明质酸降解为小片段。糖尿病患者糖萼的大小和通透性发生改变。此外，1型糖尿病患者血浆中HA和HYAL1水平均升高。为了研究HYAL1在糖尿病诱导的内皮功能障碍发展中的潜在意义，我们测量了野生型和HYAL1敲除（KO）小鼠的内皮标志物、内皮依赖性血管舒张、小动脉糖盏大小和肾小球屏障特性，这些小鼠有或没有链脲佐菌素（STZ）诱导的糖尿病。我们观察到，注射STZ 4周后，缺乏HYAL1(1)可防止糖尿病诱导的可溶性p -选择素浓度增加，并限制疾病对内皮依赖性超极化（EDH）介导的血管舒张的影响；2)糖尿病患者增加糖萼厚度，维持糖萼结构和HA含量；3)通过尿白蛋白与肌酐比值和尿70- 40 kda葡聚糖比值评估预防糖尿病引起的肾小球屏障功能障碍。我们的研究结果表明，HYAL1参与糖尿病诱导的内皮和糖萼功能障碍。HYAL1抑制剂可作为预防糖尿病血管并发症的一种新的治疗途径。
Hyaluronic acid (HA) is a major component of the glycocalyx involved in the vascular wall and endothelial glomerular permeability barrier. Endocytosed hyaluronidase HYAL1 is known to degrade HA into small fragments in different cell types, including endothelial cells. In diabetes, the size and permeability of the glycocalyx are altered. In addition, patients with type 1 diabetes present increased plasma levels of both HA and HYAL1. To investigate the potential implication of HYAL1 in the development of diabetes-induced endothelium dysfunction, we measured endothelial markers, endothelium-dependent vasodilation, arteriolar glycocalyx size, and glomerular barrier properties in wild-type and HYAL1 knockout (KO) mice with or without streptozotocin (STZ)-induced diabetes. We observed that 4 weeks after STZ injections, the lack of HYAL1 1) prevents diabetes-induced increases in soluble P-selectin concentrations and limits the impact of the disease on endothelium-dependent hyperpolarization (EDH)mediated vasorelaxation; 2) increases glycocalyx thickness and maintains glycocalyx structure and HA content during diabetes; and 3) prevents diabetes-induced glomerular barrier dysfunction assessed using the urinary albumin-to-creatinine ratio and urinary ratio of 70- to 40-kDa dextran. Our findings suggest that HYAL1 contributes to endothelial and glycocalyx dysfunction induced by diabetes. HYAL1 inhibitors could be explored as a new therapeutic approach to prevent vascular complications in diabetes.