Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells - A potential role in the pathogenesis of proteinuria in diabetic patients
Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells - A potential role in the pathogenesis of proteinuria in diabetic patients
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DOI：
10.2337/diabetes.54.7.2172
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发表时间：
2005-07-01
期刊：
影响因子：
7.7
通讯作者：
Xu, XL
中科院分区：
文献类型：
--
作者：
Maxhimer, JB;Somenek, M;Xu, XL
糖尿病肾病肾脏肾小球基底膜（GBM）硫酸乙酰肝素蛋白多糖下调的分子机制仍存在争议。在本研究中，我们发现糖尿病肾病肾脏的肾上皮细胞中乙酰肝素酶-1（HPR1）（一种硫酸乙酰肝素降解内切糖苷酶）的表达上调。糖尿病肾病患者的尿液 HPR1 水平升高。体外细胞培养研究表明，高糖条件下肾上皮细胞中 HPR1 启动子驱动的荧光素酶报告基因表达、HPR1 mRNA 和蛋白质上调。高葡萄糖诱导 HPR1 表达导致细胞表面硫酸乙酰肝素表达减少。 HPR1 抑制剂能够恢复细胞表面硫酸乙酰肝素的表达。功能分析表明，在高葡萄糖条件下生长的肾上皮细胞导致基底膜对白蛋白的通透性增加。我们的研究表明，糖尿病肾病 GBM 中硫酸乙酰肝素的丢失可归因于 HPR1 表达增加导致硫酸乙酰肝素加速降解。
The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate-degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter-driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression.