Saito Yoshihiko
Department of Cardiovascular Medicine, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan.
J Mol Cell Cardiol. 2021 Feb;151:106-112. doi: 10.1016/j.yjmcc.2020.10.001. Epub 2020 Oct 9.
Although the concept of the cardiorenal connection is widely accepted, athe underlying molecular mechanism has not been clearly defined. Nevertheless, accumulating evidence indicates that the nervous system and both the humoral and cellular immune systems are all involved. This review article focuses on the roles of the signaling pathway of placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), in the development of the cardiorenal connection. PlGF, a member of the vascular endothelial cell growth factor family, is a specific ligand for Flt-1 and plays roles in the development of atherosclerosis, wound healing after ischemia injury, and angiogenesis through Flt-1 signaling. Flt-1, a tyrosine-kinase type receptor with a single transmembrane domain, has a soluble isoform (sFlt-1) consisting of only extracellular domains, and is an intrinsic antagonist of PlGF. In renal dysfunction, PlGF is upregulated and sFlt-1 is downregulated by oxidative stress or uremic toxins, leading to activation of the PlGF/Flt-1 signaling pathway, which in turn plays a role in the worsening of atherosclerosis and heart failure, both of which are frequently associated with renal dysfunction. Monocyte chemotactic protein-1 (MCP-1) is involved in the process downstream of the Flt-1 signaling pathway. Plasma levels of sFlt-1 correlate with the severity of renal dysfunction in patients with heart failure or myocardial infarction, and are associated with the incidence of cardiovascular events. This is inconsistent with the concept of relative activation of the PlGF/Flt-1 pathway in renal dysfunction. However, the level of circulating sFlt-1 does not always parallel sFlt-1 synthesis, probably because sFlt-1 is stored on cell surfaces through its heparin-binding domains and its quantity is regulated differently in renal dysfunction. This review summarizes a novel concept wherein noninfectious inflammation via PlGF/Flt-1 signaling is involved in the development of renal dysfunction-related cardiovascular complications.
尽管心肾联系的概念已被广泛接受，但其潜在的分子机制尚未明确界定。然而，越来越多的证据表明，神经系统以及体液和细胞免疫系统均参与其中。这篇综述文章重点关注胎盘生长因子（PlGF）及其受体——类fms酪氨酸激酶-1（Flt-1）的信号通路在建立心肾联系中的作用。PlGF是血管内皮细胞生长因子家族的成员，是Flt-1的特异性配体，通过Flt-1信号通路在动脉粥样硬化的发展、缺血性损伤后的伤口愈合以及血管生成中发挥作用。Flt-1是一种具有单个跨膜结构域的酪氨酸激酶型受体，有仅由细胞外结构域组成的可溶性异构体（sFlt-1），是PlGF的内源性拮抗剂。在肾功能不全时，氧化应激或尿毒症毒素会使PlGF上调而sFlt-1下调，导致PlGF/Flt-1信号通路激活，进而在动脉粥样硬化和心力衰竭的恶化中发挥作用，这两种情况都常与肾功能不全相关。单核细胞趋化蛋白-1（MCP-1）参与Flt-1信号通路的下游过程。心力衰竭或心肌梗死患者血浆中sFlt-1水平与肾功能不全的严重程度相关，并与心血管事件的发生率有关。这与肾功能不全时PlGF/Flt-1通路相对激活的概念不一致。然而，循环中sFlt-1的水平并不总是与sFlt-1的合成平行，可能是因为sFlt-1通过其肝素结合结构域存储在细胞表面，其数量在肾功能不全时受到不同调节。这篇综述总结了一个新的概念，即通过PlGF/Flt-1信号传导的非感染性炎症参与了与肾功能不全相关的心血管并发症的发生发展。
