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.

尽管心肾连接的概念已被广泛接受，但其潜在的分子机制尚未明确定义。尽管如此，越来越多的证据表明神经系统以及体液和细胞免疫系统都参与其中。这篇综述文章重点介绍胎盘生长因子 (PlGF) 及其受体 fms 样酪氨酸激酶-1 (Flt-1) 的信号通路在心肾连接发展中的作用。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，在动脉粥样硬化的发展、缺血损伤后的伤口愈合和通过 Flt-1 信号传导的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，具有仅由细胞外结构域组成的可溶性同种型 (sFlt-1)，并且是PlGF的内在拮抗剂。在肾功能障碍中，氧化应激或尿毒症毒素使 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起作用，两者均常与肾功能不全有关。单核细胞趋化蛋白-1 (MCP-1) 参与 Flt-1 信号通路下游的过程。sFlt-1 的血浆水平与心力衰竭或心肌梗死患者肾功能障碍的严重程度相关，并与心血管事件的发生率相关。这与肾功能障碍中 PlGF/Flt-1 通路相对激活的概念不一致。然而，循环 sFlt-1 的水平并不总是与 sFlt-1 合成平行，可能是因为 sFlt-1 通过其肝素结合域储存在细胞表面，并且其数量在肾功能障碍中受到不同的调节。本综述总结了一个新概念，其中通过 PlGF/Flt-1 信号传导的非感染性炎症参与了肾功能障碍相关心血管并发症的发展。