Department of Pathology, Leiden University Medical Center, L1Q, Room P0-107, 2300 RC, Leiden, The Netherlands.
Department of Obstetrics and Gynaecology, Leiden University Medical Center, Leiden, The Netherlands.
Sci Rep. 2021 Mar 11;11(1):5692. doi: 10.1038/s41598-021-85040-9.
The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETR blockade, but not dual ETR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.
内皮糖蛋白血栓调节蛋白调节凝血、血管炎症和细胞凋亡。在肾脏中，血栓调节蛋白通过引发肾小球内皮细胞和足细胞之间的串扰来保护肾小球滤过屏障。几种肾小球病变的特征是肾小球血栓调节蛋白的丢失。在子痫前期妇女中，血清可溶性血栓调节蛋白水平升高，可能反映了肾小球内皮细胞的丢失。我们着手研究子痫前期妇女和暴露于血管生成抑制剂的大鼠肾脏中血栓调节蛋白表达是否降低。使用免疫组织化学和 qPCR 检查了 11 例子痫前期妇女、22 例妊娠对照者和 11 例高血压非妊娠妇女的肾脏尸检组织中的血栓调节蛋白表达。此外，还研究了接受不同剂量舒尼替尼或舒尼替尼联合内皮素受体拮抗剂治疗的大鼠的肾脏。子痫前期妇女肾脏中的肾小球血栓调节蛋白蛋白水平增加。平行地，在暴露于舒尼替尼的大鼠中，肾小球血栓调节蛋白呈剂量依赖性上调，并且肾小球血栓调节蛋白的上调先于组织病理学变化的发生。选择性 ETR 阻断，但不是双重 ETR 阻断，可使舒尼替尼诱导的血栓调节蛋白表达增加和白蛋白尿正常化。我们提出，在抗血管生成条件诱导的早期肾损伤中，肾小球血栓调节蛋白表达增加。肾小球内皮细胞中这种肾保护蛋白的上调可能作为保护子痫前期肾小球滤过屏障的机制。
