The role of the PlGF/Flt-1 signaling pathway in the cardiorenal connection
Introduction
Numerous interactions between organs are necessary to maintain health, and their disruption leads to vicious cycles of disease. Although every organ may be involved in disease development, certain organs demonstrate a particularly close relationship with each other. Clinically, heart failure (HF) and renal dysfunction frequently coincide. About 50%–75% of patients with acute HF also have preexisting chronic kidney disease (CKD), which is one of the major risk factors for the development and worsening of HF [[1], [2], [3], [4]]. Thus, there is a very close interaction between the heart and kidneys and is referred to as the cardiorenal connection or cardiorenal syndrome [5,6]. The underlying mechanism responsible for the cardiorenal connection is thought to involve physiological or hemodynamic alterations. However, this mechanism is currently recognized to be highly complex and involves imbalances between the nervous, endocrine, paracrine, inflammatory, and immune systems, induced by cardiac or kidney dysfunction [7].
This review focuses on the means by which the signaling pathway of placental growth factor (PlGF), acting through its receptor, fms-like tyrosine kinase-1 (Flt-1), plays a role in the development of the type of cardiorenal connection in which chronic renal dysfunction precedes cardiac dysfunction.
Section snippets
PlGF
The signaling system of the vascular endothelial cell growth factor (VEGF) family consists of five ligands—VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D—and three tyrosine kinase receptors—VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and VEGFR-3 (Flt-4). The roles of this system in angiogenesis, neuronal regulation, and lymphangiogenesis during fetal development have been well studied, and are also being investigated in the context of tumor development and other ischemic and inflammatory diseases [8,9].
Circulating PlGF in CKD
In patients with CKD, who usually experience worsening of arteriosclerosis and atherosclerosis, plasma PlGF levels are positively correlated with the severity of CKD [16,17]. PlGF was found to be a predictor of all-cause mortality and cardiovascular events, even after adjusting for traditional predictors such as age, CKD stage, and levels of brain natriuretic peptide (BNP). When patients with CKD were divided into four subgroups according to plasma PlGF levels, those in the highest quartile
Worsening of atherosclerosis in 5/6-nephrectomized Apo E−/− mice
Onoue et al. [19] performed an in vivo experiment using 5/6 nephrectomized Apo E−/− mice and found that sFlt-1 mRNA was downregulated in the kidneys and lungs, plasma sFlt-1 level was lower, and plasma PlGF level was higher in the experimental mice than that in the control Apo E−/− mice. Furthermore, the 5/6-nephrectomized mice had significantly larger plaque areas in the thoracoabdominal aorta and aortic root, with massive infiltration of macrophages into the plaques (Fig. 4). These results
Circulating PlGF and sFlt-1 in coronary artery disease
This section reviews the pathological significance of PlGF/Flt-1 signaling in the development of coronary artery disease, a typical atherosclerotic disease. Although few studies have reported that plasma levels of either PlGF or sFlt-1 alone are good markers to determine the severity of coronary artery disease, the ratio of PlGF to sFlt-1 was shown to positively correlate with disease severity and was also considered to be a good marker for cardiac outcomes [24]. In patients with chronic
Circulating PlGF in HF
To understand the pathophysiological significance of PlGF/Flt-1 signaling in the cardiorenal connection, it is important to evaluate the expression profiles of PlGF and sFlt-1 in HF. This is because about 50% of patients with HF have accompanying renal dysfunction with an eGFR <60 mL/min/1.73 m2, and around 20%–30% of patients have an eGFR <30 mL/min/1.73 m2 [[1], [2], [3], [4]]. In patients with chronic HF, plasma PlGF levels increase roughly in parallel with HF severity. Plasma PlGF levels
The role of the imbalance between PlGF and sFlt-1 in the cardiorenal connection
The imbalance between PlGF and sFlt-1 has been well investigated in preeclampsia. In physiological pregnancy, PlGF and sFlt-1 are upregulated to maintain placental function [37,38]. However, in cases of placental hypoxia or impaired perfusion, trophoblasts produce massive amounts of sFlt-1 and suppress PlGF production in the placenta. sFlt-1 is abundantly synthesized in the placenta and circulates systemically in the mother; its plasma levels are more than ten-fold higher than those of PlGF in
Funding sources
This work was supported in part by MEXT KAKENHI Grant Number JP19155855 (Grants-in-aid from the Ministry of Education, Culture, Sports and Science).
Declaration of Competing Interest
Yoshihiko Saito has received the following: research funds from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Actelion Pharmaceuticals Japan, Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Teijin Pharma, Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Medi-Physics
Acknowledgement
We thank Kenji Onoue, Masru Matsui, Shiro Uemura, Yukiji Takeda, Hajime Iwama, Ayako Seno, Takaki Matsumoto, and Yasuki Nakada for their help and discussions during the preparation of the manuscript, and Mari Miyagawa for her secretarial work.
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