The number of patients with chronic kidney disease (CKD) has been increasing globally, and these individuals currently comprise more than 10% of the general population in developed countries [1]. CKD is associated with two critical risks: the progression of end-stage renal disease and the development of cardiovascular diseases. The death rate due to cardiovascular diseases exceeds the rate of progression to more severe nephropathy in diabetic kidney disease [2]. The coexistence of cardiovascular and renal disease is associated with a higher risk of cardiovascular events and death than the presence of either condition alone [3]. Organ cross-talk between the heart and kidneys is widely recognized, and is referred to as the “cardiorenal connection” [4]. The molecular mechanisms underlying this phenomenon are not fully understood, but the natriuretic peptide family and fibroblast growth factors have been established as leading players in the pathogenesis of cardiac hypertrophy and vascular calcification in CKD ^[5][6][5,6]. Recently, however, the cardiorenal connection has been shown to be increasingly complex since several underlying mechanisms have been identified; these include endothelial injury, immunological imbalance, cell death, inflammatory cascades, and oxidative stress [7].

2. PlGF/Flt-1 Pathway

2.1. PlGF

The human vascular endothelial growth factor (VEGF) family consists of two groups of molecules: VEGF-A, VEGF-B, and placental growth factor (PlGF)PlGF, which are primarily involved in the growth of blood vessels [8]; and VEGF-C and VEGF-D, which contribute mainly to the growth of lymphatic vessels [9]. VEGF ligands can form anti-parallel homodimers and heterodimers that optimize binding to these ligands’ preferred receptors and facilitate receptor dimerization [10]. VEGF-associated receptors (VEGFR-1, also known as Flt-1; VEGFR-2, also known as Flk-1 in mice and KDR in humans; and VEGFR-3, also known as Flt-4) are characterized by a ligand-binding region with seven immunoglobulin-like domains, a single transmembrane domain, and a tyrosine kinase domain with a long kinase insert (Figure 1). VEGF-A, VEGF-C, and VEGF-D bind to Flt-1 and Flk-1, while PlGF and VEGF-B bind only to Flt-1. The VEGF family plays a wide variety of crucial roles in the regulation of angiogenesis, lymphangiogenesis, lipid metabolism, inflammation, atherosclerosis, and tumor development ^[11][12][11,12]. Two years after VEGF was identified, PlGF was first discovered in the human placenta, where it is highly expressed in trophoblasts and endothelial cells and promotes placental growth [13]. PlGF was later found to be expressed in many other organs, such as the heart, lungs, and brain ^[14][15][16][14,15,16]. Unlike VEGF, PlGF is redundant for vascular development and physiological vessel maintenance in healthy adults, and it is highly expressed in pathological conditions such as malignancy, tissue ischemia, and inflammation [17]. Experimental studies showed that local delivery of the PlGF gene into the carotid artery of hypercholesterolemic rabbits enhanced intimal thickening via macrophage accumulation [18]. Moreover, treatment with a neutralizing monoclonal antibody against PlGF reduced the inflammatory cell infiltration and attenuated the development of atherosclerotic lesions in Apo E KO mice [19].

2.2. Flt-1 and the Soluble Isoform of Flt-1 (sFlt-1)

In 1990, a novel tyrosine kinase receptor, later known as Flt-1, was originally isolated from the human placenta by Shibuya [20]. Unlike Flk-1, the affinity of Flt-1 for its ligand, VEGF, is very high, and is at least 10-fold higher than that for VEGFR-2 [21]. However, the kinase activity of VEGFR-1 is lower, about one-tenth that of VEGFR-2 ^[20][22][20,22]. Flt-1 is primarily expressed on vascular endothelial cells, and it functions mainly to regulate blood vessel angiogenesis, maintenance, and permeability, as well as endothelial cell migration and proliferation ^[10][23][24][10,23,24]. Its expression on non-vascular cells further supports the non-vascular biological roles of VEGF and PlGF ^[25][26][25,26]. Flt-1 also contributes to the migration and activation of monocytes and macrophages, leading to inflammatory processes and angiogenesis. In 1993, Kendall reported that a soluble isoform of Flt-1 (sFlt-1) mRNA covers six Ig regions of the full-length Flt-1, with a 31 amino acid–long tail derived from intron 13 [22]. Later investigations reported Flt-1 isoforms that are generated by alternative splicing of exons 14 and 15 ^[27][28][27,28] and by shedding of the Flt-1 extracellular domain ^[29][30][29,30]. sFlt-1 traps PlGF and VEGF-A and acts as a negative regulator of both molecules. These molecular mechanisms indicate that PlGF is pro-atherogenic, while sFlt-1, an intrinsic PlGF antagonist, is anti-atherogenic.

3. PlGF/sFlt-1 Imbalance in CKD

3.1. Circulating PlGF in CKD

Circulating levels of PlGF are normally undetectable, but increased PlGF levels have been described under pathological conditions [31]. In CKD patients, serum levels of PlGF are directly correlated with CKD severity [32] and the left ventricular mass index [33]. It can b  We found that increasing PlGF levels were associated with an increased risk of both mortality and cardiovascular events, the latter defined as atherosclerotic diseases and heart failure (HF) requiring hospitalization: the risks for patients in the highest quartile (≥19.6 pg/mL) were 3.87- and 8.42-fold higher, respectively, than for those in the lowest quartile (<10.1 pg/mL) [32]. Higher levels of PlGF and greater CKD severity were independently and additively associated with an increased risk of mortality and cardiovascular events (Figure 2).

3.2. PlGF Production in CKD

In a remnant kidney model, PlGF mRNA and protein expression were upregulated not only in the kidneys but also in other organs ^[34][35][36][34,35,36]. The expression of PlGF in cultured human umbilical arterial endothelial cells was also increased by the addition of human serum from patients with advanced CKD, which also upregulated biomarkers for endothelial injury and oxidative stress. However, treatment with the antioxidant vitamin E attenuated PlGF production [35]. These data suggest that upregulation of PlGF in CKD contributes to the development of arteriosclerotic diseases or HF via augmentation of vascular inflammation and permeability. Activation of mineralocorticoid receptors by aldosterone induces early atherosclerosis and promotes plaque inflammation via increased PlGF secretion from vascular cells [37]. Recently, treatment with a novel selective nonsteroidal mineralocorticoid receptor antagonist, finerenone, reduced the risks of cardiovascular events in patients with diabetic kidney disease ^[38][39][38,39]. This beneficial effect of finerenone in CKD may contribute to the suppression of PlGF/Flt-1 signaling.

4. Role of PlGF/sFlt-1 Imbalance

An in vivo experiment using 5/6-nephrectomized Apo E knockout (KO) mice showed that mRNA and plasma levels of sFlt-1 were decreased but those of PlGF were increased compared with the control Apo E KO mice ^[35][36][35,36]. The CKD model mice had more areas with severe plaque in the thoracoabdominal aorta and aortic root, with massive infiltration of macrophages into the plaques. These atherosclerotic lesions were positively related to plasma levels of indoxyl sulfate and p-cresol ^[40][45]. Treatment with AST120, an oral carbon adsorbent of uremic toxins, was inversely related to atherosclerosis in CKD model mice and was also associated with an increase in sFlt-1 production. Additionally, repeated administration of recombinant human sFlt-1 comprising the first three immunoglobulin-like domains of the extracellular region of Flt-1 resulted in significant decreases in plaque area and macrophage infiltration (Figure 34).