乙酰肝素酶
足细胞
糖萼
内分泌学
内科学
内皮素受体
糖尿病肾病
硫酸乙酰肝素
内皮素1
蛋白尿
受体
医学
化学
细胞生物学
生物
糖尿病
肾
肝素
作者
Marjolein Garsen,Olivia Lenoir,Angelique L. Rops,Henry Dijkman,Brigith Willemsen,Toin H. Van Kuppevelt,Ton J. Rabelink,Jo H. M. Berden,Pierre‐Louis Tharaux,Johan van der Vlag
出处
期刊:Journal of The American Society of Nephrology
日期:2016-03-29
卷期号:27 (12): 3545-3551
被引量:101
标识
DOI:10.1681/asn.2015091070
摘要
Diabetic nephropathy (DN) is the leading cause of CKD in the Western world. Endothelin receptor antagonists have emerged as a novel treatment for DN, but the mechanisms underlying the protective effect remain unknown. We previously showed that both heparanase and endothelin-1 are essential for the development of DN. Here, we further investigated the role of these proteins in DN, and demonstrated that endothelin-1 activates podocytes to release heparanase. Furthermore, conditioned podocyte culture medium increased glomerular transendothelial albumin passage in a heparanase-dependent manner. In mice, podocyte-specific knockout of the endothelin receptor prevented the diabetes-induced increase in glomerular heparanase expression, consequent reduction in heparan sulfate expression and endothelial glycocalyx thickness, and development of proteinuria observed in wild-type counterparts. Our data suggest that in diabetes, endothelin-1 signaling, as occurs in endothelial activation, induces heparanase expression in the podocyte, damage to the glycocalyx, proteinuria, and renal failure. Thus, prevention of these effects may constitute the mechanism of action of endothelin receptor blockers in DN.
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