Department of Internal Medicine D, University Hospital Münster, Münster, Germany; Small Animal Hospital, University of Veterinary Medicine Hannover, Hannover, Germany.
Department of Internal Medicine D, University Hospital Münster, Münster, Germany.
Kidney Int. 2019 May;95(5):1091-1102. doi: 10.1016/j.kint.2018.11.023. Epub 2019 Feb 26.
Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.
肾缺血再灌注损伤（IRI）会对肾移植后的临床结果产生不利影响。了解 IRI 后的细胞机制和基因/蛋白质表达的变化可能有助于改善这些结果。血清可溶性 fms 样酪氨酸激酶 1（sFlt-1）是一种循环抗血管生成蛋白，在肾移植后第一周内增加。我们在 93 名肾移植受者的纵向研究中和在几个动物模型中评估了升高的 sFlt-1 水平与 IRI 后肾微血管功能障碍的因果关系。sFlt-1 水平较高的移植受者发生延迟移植物功能、移植物排斥、移植物功能受损和死亡的几率更高。在 25 名接受肾移植后 4 个月内行肾活检的参与者亚组中，血清 sFtl-1 水平升高者的肾小管周围毛细血管面积较低。将重组 sFlt-1 注入啮齿动物会导致肾微血管的结构和功能发生显著变化，包括肾小管周围毛细血管密度降低和毛细血管内血液体积减少，并导致炎症基因表达增加和纤维化增加。在 IRI 的小鼠模型中，肾脏是 sFlt-1 产生的部位，而 sFlt-1 的系统中和可保留肾小管周围毛细血管密度并减轻肾纤维化。我们的数据表明，IRI 后高水平的 sFlt-1 在微血管功能障碍的发病机制中起重要作用，从而导致肾移植后的不良临床结果。
