Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells
Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells
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DOI：
10.1016/j.kint.2019.05.007
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发表时间：
2019-10-01
影响因子：
19.6
通讯作者：
Daehn, Ilse
中科院分区：
文献类型：
--
作者：
Ebefors, Kerstin;Wiener, Robert J.;Daehn, Ilse
在病理情况下肾小球细胞之间相互作用的新证据为新的治疗方法的发现提供了机会。在此我们研究了在原发性足细胞病（足细胞特异性转化生长因子 -β受体1信号激活）或阿霉素肾病小鼠模型中导致足细胞滤过屏障缺陷以及足细胞和肾小球内皮细胞相互作用的早期事件的潜在机制。我们发现肾小球内皮表面层降解和蛋白尿先于足细胞足突消失。这些异常可通过内皮素受体 -A拮抗剂和线粒体活性氧清除来预防。进一步的研究证实，响应足细胞释放的因子和内皮素 -1，肾小球内皮细胞中乙酰肝素酶和透明质酸葡萄糖苷酶基因表达增加。原子力显微镜测量显示内皮素 -1和足细胞释放的因子可使内皮表面层显著减少，这可通过内皮素受体 -A拮抗剂而非内皮素受体 -B拮抗剂来预防。因此，我们的研究提供了活化的足细胞和肾小球内皮细胞之间早期相互作用的证据，这种相互作用导致内皮表面层丧失、肾小球内皮细胞损伤和蛋白尿。因此，内皮素 -1 - 内皮素受体 -A的激活和线粒体活性氧参与了实验性局灶节段性肾小球硬化中原发性足细胞病的发病机制。
Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-beta receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondria! reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.