Endothelial Nitric Oxide Synthase Prevents Heparanase Induction and the Development of Proteinuria.
Endothelial Nitric Oxide Synthase Prevents Heparanase Induction and the Development of Proteinuria.
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DOI：
10.1371/journal.pone.0160894
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
van der Vlag J
中科院分区：
文献类型：
--
作者：
Garsen M;Rops AL;Li J;van Beneden K;van den Branden C;Berden JH;Rabelink TJ;van der Vlag J
内皮一氧化氮合酶（eNOS）缺乏会加剧多种肾小球疾病中的蛋白尿和肾损伤，但其潜在机制尚不完全清楚。我们最近发现乙酰肝素酶对于实验性糖尿病肾病和肾小球肾炎的发展至关重要，并假设乙酰肝素酶的表达受 eNOS 调节。在这里，我们证明，在 C57BL/6 eNOS 缺陷小鼠中诱导阿霉素肾病 (AN) 会导致肾小球乙酰肝素酶表达增加，并伴有明显的蛋白尿，而在 AN 抗性野生型小鼠中未观察到这种情况。在体外，eNOS 抑制剂不对称二甲基精氨酸 (ADMA) 诱导培养的小鼠肾小球内皮细胞中乙酰肝素酶的表达。此外，ADMA 以乙酰肝素酶依赖性方式增强跨内皮白蛋白通道。我们得出结论，eNOS 可以防止乙酰肝素酶诱导和蛋白尿的发生。
Endothelial nitric oxide synthase (eNOS) deficiency exacerbates proteinuria and renal injury in several glomerular diseases, but the underlying mechanism is not fully understood. We recently showed that heparanase is essential for the development of experimental diabetic nephropathy and glomerulonephritis, and hypothesize that heparanase expression is regulated by eNOS. Here, we demonstrate that induction of adriamycin nephropathy (AN) in C57BL/6 eNOS-deficient mice leads to an increased glomerular heparanase expression accompanied with overt proteinuria, which was not observed in the AN-resistant wild type counterpart. In vitro, the eNOS inhibitor asymmetric dimethylarginine (ADMA) induced heparanase expression in cultured mouse glomerular endothelial cells. Moreover, ADMA enhanced transendothelial albumin passage in a heparanase-dependent manner. We conclude that eNOS prevents heparanase induction and the development of proteinuria.