The role of the PlGF/Flt-1 signaling pathway in the cardiorenal connection

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.