ReviewThe Cardiorenal Syndrome-Integrative and Cellular Mechanisms

Vasculopathy in the setting of cardiorenal syndrome: roles of protein-bound uremic toxins

Abstract

Chronic kidney disease (CKD) often leads to and accelerates the progression of cardiovascular disease (CVD), while CVD also causes kidney dysfunction. This bidirectional interaction leads to the development of a complex syndrome known as cardiorenal syndrome (CRS). CRS not only involves both the heart and the kidney but also the vascular system through a vast array of contributing factors. In addition to hemodynamic, neurohormonal, mechanical, and biochemical factors, nondialyzable protein-bound uremic toxins (PBUTs) are also key contributing factors that have been demonstrated through in vitro, in vivo, and clinical observations. PBUTs are ineffectively removed by hemodialysis because their complexes with albumins are larger than the pores of the dialysis membranes. PBUTs such as indoxyl sulfate and p-cresyl sulfate are key determinate and predictive factors for the progression of CVD in CKD patients. In CRS, both vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) exhibit significant dysfunction that is associated with the progression of CVD. PBUTs influence proliferation, calcification, senescence, migration, inflammation, and oxidative stress in VSMCs and ECs through various mechanisms. These pathological changes lead to arterial remodeling, stiffness, and atherosclerosis and thus reduce heart perfusion and impair left ventricular function, aggravating CRS. There is limited literature about the effect of PBUT on the vascular system and their contribution to CRS. This review summarizes current knowledge on how PBUTs influence vasculature, clarifies the relationship between uremic toxin-related vascular disease and CRS, and highlights the potential therapeutic strategies of uremic vasculopathy in the setting of CRS.

chronic kidney disease (CKD) and the accompanied accumulation of uremic toxins lead to and accelerate the pathology of cardiovascular disease (CVD), while CVD, especially heart failure, also directly causes kidney dysfunction. This complex relationship is better known as cardiorenal syndrome (CRS) (49, 121). The first report, published 42 yr ago, showed that a high proportion of CKD patients died from arteriosclerotic complications, such as myocardial infarction, stroke, and refractory congestive heart failure (80). Subsequent studies showed that those diagnosed with primary CKD demonstrated increased atherosclerotic development, CVD morbidity, and an ~20-fold increase in the risk of cardiovascular death (25, 128).

Atherosclerosis does play an important role in uremic vasculopathy. Studies have shown that uremic toxins participate in atherosclerosis in the following steps: 1) adhesion between endothelial cells (ECs) and activated leukocytes, 2) migration and proliferation of vascular smooth muscle cells (VSMCs) stimulated by local inflammation, and finally 3) formation of atherosclerotic plaque and subsequent rupture of the fibrous cap activates thrombotic events (18), which decreases or stops the blood supply to the target organs. This leads to myocardial ischemia or necrosis, together with myocardial hypertrophy (73), in which there is an increase in extracellular matrix, leading to interstitial cardiac fibrosis (89). This increases left ventricular (LV) stiffness and decreases diastolic function (85). A recent clinical study showed that greater levels of indoxyl sulfate (IS) in plasma-aggravated LV diastolic dysfunction (129), which was associated with higher mortality in CKD than in cases with systolic dysfunction (4). However, LV diastolic dysfunction eventually leads to systolic dysfunction, mainly manifesting as lower cardiac output and nephritic perfusion, aggravating CRS. Therefore, vasculopathy may play a critical role in CRS development and progression.

While hemodialysis removes the majority of uremic toxins, it is unable to effectively remove those with a high protein binding capacity. Protein-bound uremic toxins (PBUTs), such as IS, were the first principal serum metabolites shown to differentiate CKD from others with normal kidney function, followed by p-cresyl sulfate (p-CS) (63). Both of these PBUTs possess very high protein binding capacity of >90% with albumin (58); there is a dynamic balance between the protein-bound form and free form (153). As a result, the molecular complexes formed by the protein-bound aggregate are too large to pass through dialysis membranes, resulting in a low reduction rate of <35% (58), leading to continued systemic accumulation of these uremic toxins after hemodialysis.

There are 25 uremic retention solutes that have been classified as PBUTs in the European Uremic Toxin Work Group study in 2003 (Table 1) (151). IS and p-CS are two of the most important PBUTs and therefore have been widely studied in both cardiovascular and renal systems. IS and p-CS are metabolic products of amino acids such as tryptophan, tyrosine, and phenylalanine, which are commonly found within dietary protein. These amino acids are converted by colonic microflora into indole and p-cresol and further metabolized into IS and p-CS, respectively, within the liver (162). Both IS and p-CS concentrations are powerful predictors of overall cardiovascular mortality and accurately reflect the progression of CVD in CKD patients (12, 74). Serum IS or p-CS levels are independently associated with the presence and severity of coronary artery disease (CAD) (51, 157). Similarly, both IS and p-CS are associated with peripheral artery disease (PAD) (77). In addition, a study (148) on percutaneous coronary intervention showed that free IS was an independent predictor for coronary restenosis in patients with drug-eluting stent implantations. The serum IS concentration is ~249 µM (110) to 360 µM (111) in CKD patients, and its level increases progressively with increasing CKD stages (78); serum levels of IS and p-CS can be as high as ~939.1 µM (143, 151) and 531.3 µM (118, 131), respectively, in hemodialysis patients. Most of the concentrations of uremic toxins used in the studies cited in this review were within this range.

Table 1. Protein-bound uremic toxins classified in the European Uremic Toxin Work Group study in 2003

Group/SoluteMolecular Weight
Advanced glycation end products
    3-Deoxyglucosone162
    Fructoselysine308
    Glyoxal58
    Methylglyoxal72
 Nε-(carboxymethyl) lysine204
    Pentosidine342
Hippurates
    Hippuric acid179
 p-Hydroxy-hippuric acid195
Indoles
    Indole-3-acetic acid175
    Indoxyl sulfate251
    Kinurenine208
    Kynurenic acid189
    Melatonin126
    Quinolinic acid167
Peptides
    Leptin16,000
    Retinol-binding protein21,200
Phenols
    2-Methoxyresorcinol140
    Hydroquinone110
 p-Cresol/p-cresyl sulfate108
    Phenol94
Polyamines
    Putrescine88
    Spermidine145
    Spermine202
Others
    3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid240
    Homocysteine135

Current research has been focused primarily on the effects of PBUTs on the heart and/or renal systems only, with limited research focusing on their effects on vascular diseases. However, there have been a few studies on IS and p-CS in the setting of vascular disease, which identified their significant pathological effects on the vasculature and their ability to induce vessel toxicity and damage (71). This is a topic that has often been overlooked, and, as such, there are only a few studies about other PBUTs and their effects on vascular disease. This review will summarize currently available knowledge on how key PBUTs, IS and p-CS, influence the vasculature (Fig. 1) as well as identify possible therapeutic strategies for PBUT-induced vasculopathy.

Fig. 1.

Fig. 1.Indoxyl sulfate (IS) and p-cresyl sulfate (p-CS) from metabolism to pathological effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). The amino acids tryptophan and tyrosine, from dietary protein, are decomposed into indole and p-cresol in the colon, which are further metabolized into IS and p-CS in the liver. IS and p-CS are accumulated in chronic kidney disease patients. Circulating IS and p-CS bind to albumin in the vessel, forming molecular complexes that are too large to pass through dialysis membranes, leading to further accumulation in the vessel/circulation, causing pathological effects on VSMCs and ECs.


Roles of PBUTs in the Pathophysiology of Vascular Intrinsic Cells

The vascular wall is composed of inner layers of ECs, outer layers of VSMCs, and an assortment of sporadic immunocytes and fibroblasts spread among them. The primary function of VSMCs is to regulate blood pressure and blood flow by controlling the luminal diameter. ECs, however, act as semiselective filters, regulating hemodynamics and inflammation. In CRS, both VSMCs and ECs exhibit significant dysfunction, leading to arterial remodeling (44), and eventually contribute to the development of atherosclerosis and vasculopathy. Arterial remodeling consists mostly of a change in the composition of the arterial wall and arterial calcification. Rats with CKD have been shown to have changes in arterial wall composition, with increased collagen and decreased elastin (108). Others have found increased proliferation of VSMCs in Dahl/Rapp salt-sensitive rats (158), and, similarly, endothelial dysfunction was found in patients (9) and animals (67) with CKD. All these factors exacerbate arterial stiffness and atherosclerosis. In addition, arterial calcification, which mainly occurs in the intima media of the arteries, is also a major complication of CKD (52). Arterial calcification reduces arterial elasticity and increases its stiffness (83), leading to elevated blood pressure and increased LV afterload, which results in LV hypertrophy. Arterial remodeling, stiffness, and calcification are mainly associated with proliferation, migration, senescence, oxidative stress, and inflammation of VSMCs and ECs.

As important vascular toxins, IS and p-CS exert their pathological effects by altering the phenotypes of both VSMCs and ECs by regulating their related gene expression. Our gene set analysis using the Gene Expression Omnibus (GEO) Database (GEO Public Database GSE52897) (109) determined the gene expression profiles of the artery in adenine-induced CKD rat models (Fig. 2). The altered gene expression profiles shown are primarily involved in the processes of the stress response, collagen synthesis, osteoblastic differentiation, and senescence. A clear relationship among altered phenotypes, pathophysiology, and potential mechanisms was demonstrated by this analysis.

Fig. 2.

Fig. 2.Enrichment analysis for different expression of genes in the thoracic aorta of the adenine-induced chronic renal failure rat model. The heat map shows that biological processes mostly involve activation of the transforming growth factor (TGF)-β signaling pathway, MAPK signaling pathway, p53 signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, osteoclast differentiation, focal adhesion, and cell migration. The color scheme reflects the ratio of gene expression values to the mean: white is equal to the mean value, blue is lower than the mean, and red is higher than the mean. All data were derived from the GEO public database (GSE52897). All gene expression analysis was performed by Bioconductor based on the R program. Differential gene analysis was measured by significance analysis of microarrays (SAM). The target proportion of false discovery rate was 0.1. The KEGG enrichment was analyzed by the geneAnswersBuilder package with a cutoff P value of 0.05. The heat map was generated by the geneAnswersHeatmap package.


Effect of PBUTs on VSMCs.

The major effects of PBUTs on VSMCs are in regulating cellular proliferation, migration, senescence, calcification, and induction of inflammation, all of which are closely linked with the occurrence of atherosclerosis and subsequent cardiovascular events.

proliferation of vsmcs.

Normally, the turnover rate of VSMCs in the vessel wall is low. However, VSMC proliferation becomes significantly increased in the early stages of atherosclerosis, vascular injury (87), and aging (100). VSMC proliferation results in intimal hypertrophy and subsequent atherosclerosis development (46, 123, 147). In experimental renal failure rats, overproliferation of VSMCs and subsequent production of the aortic extracellular matrix lead to increased aortic wall thickness (8). In addition, overproliferation of VSMCs results in decreased aortic elastic fiber content, a phenomenon that may be responsible for increased aortic stiffness and decreased aortic compliance, as documented in patients with renal failure (82, 84).

There are a series of mechanisms involved in the proliferation of VSMCs. Of these, IS has been shown to directly promote rat VSMC proliferation in vitro. IS-induced VSMC proliferation has been ascribed to multiple mechanisms, including a heightened uptake by organic anion transporter 3 (OAT-3) on VSMCs (169) and activation of the p44/42 MAPK pathway, which is also called the ERK1/2 pathway (5, 33, 169), via the overexpression of PDGF-C chain and PDGF-β receptors (169). IS-induced proliferation of VSMCs via the OAT/MAPK signaling pathway has been identified to be similar to that of uric acid (60, 120). In addition to the p44/42 MAPK signaling pathway, NADPH oxidase-dependent production of ROS with subsequent activation of p38 MAPK and phosphorylation of PDGF-β receptors induces proliferation and migration of VSMCs (136). Subsequently, more and more related signaling pathways for VSMC proliferation have been identified. IS stimulates VSMC proliferation possibly also through the induction of glucose transporter (GLUT)1 expression. However, increased phosphorylation of ribosomal S6 protein kinase (S6K) indicates that the mammalian target of rapamycin (mTOR)/S6K pathway, probably activated by Akt/TSC2, may also be involved in VSMC proliferation (79). IS also a potential stimulator of aortic VSMC proliferation via the activation of the (pro)renin receptor (PRR) pathway, which is a component of the renin-angiotensin system. Activation of OAT-3 increases ROS production and activation of the aryl hydrocarbon receptor (AhR) and NF-κB p65, all are involved in IS-induced expression of (pro)renin and PRR in VSMCs (170). Furthermore, (pro)renin activates ERK1/2, leading to VSMC proliferation (81). IS has also been shown to suppress expression of the Mas receptor via activation of AhR/NF-κB p65, leading to stimulation of human aortic smooth muscle cell (HASMC) proliferation (107). Conversely, some experiments have shown the inhibitory effects of IS on HASMC proliferation after long-term exposure (7 days). This paradox may be ascribed to a dose-dependent intracellular ROS induction and upregulation of p21 and p27 protein expression (101). Potential signaling pathways involved in the effects of PBUTs on VSMC proliferation are shown in Fig. 3.

Fig. 3.

Fig. 3.Signaling pathways of IS effecting on VSMC proliferation. A schematic illustration of the signaling pathways involved in the proliferation of VSMCs induced by IS is shown. The green arrow represents a positive effect to the downstream signaling molecules, and the red lines represent a negative effect. IS promotes VSMC proliferation mainly through the MAPK signaling pathway (both p38MAPK and ERK), which are possibly downstream of ROS generation. Aryl hydrocarbon receptor (AhR), PDGF, and mTOR/S6K signaling may also play an important role in the axis of proliferation regulation. PRR, (pro)renin receptor.


Other PBUTs, such as advanced glycation end products (AGEs), can also induce ROS generation leading to VSMC proliferation via interactions with the receptor for AGEs (RAGE) (171). In vivo, VSMC proliferation and migration were significantly suppressed in homozygous RAGE-null mice compared with wild-type littermates (127). Furthermore, AGEs also cause excessive expression of various extracellular matrix proteins, including fibronectin, collagen, and elastin, which can lead to decreased elasticity of the vasculature (146).

Taken together, PBUTs are some of the major contributors of overproliferation of VSMCs, which decreases aortic elastic fiber content, accompanied by increasing aortic extracellular matrix, leading to aortic stiffness, remodeling, atherosclerosis, and CVD, which leads to aggravation of CRS development and progression. There are many possible mechanisms involved in this process warranted further investigation.

calcification and osteoblastic differentiation of vsmcs.

Vascular calcification is an independent risk factor for the development of CVD (152, 155) and a reliable predictor of cardiovascular mortality in individuals with renal dysfunction (99). There is a direct relationship between serum levels of IS or p-CS and aortic calcification (12, 74). IS promotes ROS generation and enhances osteoblastic transformation of aortic smooth muscle cells via upregulation of NADPH oxidase 4 expression. This is achieved by increasing the expression of osteoblast-specific proteins, including core binding factor 1 (Cbfa1), osteopontin, and alkaline phosphatase (ALP) (102). IS also promotes osteoblastic differentiation, matrix mineralization, and calcium deposits by upregulating Pit-1 expression partially through activation of the JNK pathway in human umbilical vein ECs (HUVECs) (164).

It has been demonstrated that AGEs increase vascular calcification (161), which was reduced by inhibition of RAGE (144). This suggests that the AGE-RAGE-ROS pathway may play a critical role in vascular calcification (161). It has been shown that vascular calcification resulting from replicative senescence of VSMCs is a consequence of senescence-mediated osteoblastic transition (105).

senescence of vsmcs.

Cell senescence is the process in which diploid cells irreversibly lose their ability to divide. Senescence of VSMCs leads to depressed vascular repair and accompanied invasion of fibroblasts, together leading to vascular calcification and atherosclerosis development (13, 92). VSMC senescence was partially induced by phosphate overload (165). IS stimulates HASMC senescence by upregulating p53, p21, and prelamin A while downregulating the expression of farnesylated protein-converting enzyme 1 (FACE1) and zinc metallopeptidase STE24 (Zempste24) through oxidative stress (104). IS may induce an ongoing fibrogenic response by promoting senescence and progression of PAD and CAD.

migration of vsmcs.

The migration of VSMCs from the media layer of arteries to the intima layer is a pivotal step in the development of atherogenesis. IS-related cellular migration is induced by stimulation of the expression of ROS and PDGF-β receptors, which, in turn, activates ERK and p38 MAPK signaling pathways, respectively (14, 136). Furthermore, IS enhances ANG II-dependent ERK activation and VSMC migration by upregulating ROS-induced EGF receptor (EGFR) expression and phosphorylation (135). In summary (50, 150), the increase of EGFR expression in VSMCs may be regulated by NF-κB activation through an IS-dependent ROS production pathway. Similarly, p-CS promotes the proliferation and migration of VSMCs into atherosclerotic lesions, leading to atherosclerosis progression and reduction of plaque stability (46).

Thus, PBUTs contribute to VSMC calcification, osteoblastic differentiation, senescence, and migration, which lead to an increased risk for the arteries to undergo remodeling, stiffness, and atherogenesis, leading to CVD, which decreases global perfusion, further aggravating CRS development.

Effects of PBUTs on ECs.

Unlike VSMCs, ECs elicit their hemodynamic effects by secreting cytokines, including factors of hemodynamics and inflammation. Thus, endothelial dysfunction mainly includes the following aspects: 1) abnormal endothelium-dependent vasodilatation, accompanied by a decrease in nitric oxide (NO) production, leading to artery stiffness and calcification (23); 2) elevation of circulatory solutions representing adherence as well as inflammation, such as von Willebrand factor, tissue factor (TF), VCAM-1, and ICAM-1; and 3) variation of cellular biomarkers with endothelial microparticles (EMPs), with increased circulating ECs and decreased endothelial progenitor cells (126). All these show that an imbalance between injury and repair of the endothelium leads to endothelial dysfunction. Endothelial dysfunction has been found to be associated with renal dysfunction and contributes to the excess in cardiovascular mortality even with mild renal dysfunction (141), and it is also involved in the pathogenesis of aortic remodeling in CKD.

Due to the key role of PBUTs in endothelial dysfunction and the development of CVD (19, 122), their effects on ECs have been extensively studied. In particular, p-CS and IS have been shown to directly promote endothelial dysfunction (94).

proliferation and senescence of ecs.

The integrity of construction and metabolism in the endothelium are necessary for vascular function. ECs repair damaged blood vessels by self-proliferating and interacting with circulating cells. Patients with CKD demonstrate wound healing disturbances, partly ascribed to decreased endothelial proliferation (47). Accumulation of specific PBUTs, such as IS and p-CS, inhibits endothelial proliferation and wound repair, as demonstrated in HUVECs (31). However, these effects were less pronounced when administered with human serum albumin, presumably due to protein binding of PBUTs. Cell senescence and oxidative stress may be associated with proliferation suppression. Increased expression of senescence-related proteins, such as senescence-associated β-gal, p16INK4a, p21WAF1/CIP1, p53, and retinoblastoma protein, were observed in vivo when IS was administered (3). In addition, IS treatment in HUVECs increased cell senescence and ROS production as well as reduced cell proliferation and NO production (172). IS-induced HUVEC senescence may be attributed to damage of the iNampt-NAD+-Sir1 system via AhR activation (65). To date, only a few studies have focused on the possible antiproliferative effects of PBUTs, and further studies are warranted to comprehensively investigate the precise targets of PBUT-induced inhibition of EC proliferation and senescence.

endothelial oxidative stress.

Oxidative stress is a prominent characteristic in chronic renal failure patients (114, 159) and is closely linked to endothelial dysfunction resulting from increased lipid peroxidation products and decreased antioxidants (10). IS is the strongest ROS producer of the many known PBUTs (58). IS stimulates ROS production and NAD(P)H oxidase activity while simultaneously decreasing glutathione levels in ECs, suggesting that IS-induced oxidative stress results from impaired balance between pro- and antioxidative effects (32). Furthermore, enhancement of oxidative stress due to decreased NO levels possibly explains the mechanism of how IS induces cerebral endothelial dysfunction in the central nervous system (143). However, IS has also been shown to demonstrate an antioxidative effect by decreasing formation of 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide (EMPO)-superoxide adduct, increasing scavenging activity against neutrophil-derived superoxide anion radicals and eliminating hydroxyl radicals. This phenomenon was observed in the physiological serum concentration of IS (97). In other words, IS appears to possess a dual role of pro- and/or antioxidative properties that are concentration dependent. Further research is required to determine the specific redox properties of IS.

Similarly, p-CS induces oxidative stress in both ECs and VSMCs (44). More specifically, p-CS enhances ROS production via PKC or pathways, stimulating the production of monocyte chemoattractant protein-1 (MCP-1) and osteoblast-specific proteins, including osteopontin, ALP, and Cbfa1, leading to EC and VSMC dysfunction (160). Furthermore, p-CS has been shown to promote the formation and progression of atherosclerotic plaque via upregulation of NADPH oxidase and ROS production (59). AGEs are also involved in EC injury, probably through the effect of ROS-mediated VEGF expression (166).

inflammation of ecs.

A close relationship exists between CVD and inflammatory status. The most important is leukocyte-endothelial interactions, due to the pivotal role they play in the development of atherosclerosis (54, 122, 142). The improved ability of monocytes to adhere to the vascular endothelium and migrate into the vessel wall is an important early physiopathological changes in the pathogenesis of CVD (40, 173). IS, as well as other PBUTs, p-CS and p-cresyl glucuronide (p-CG), exert proinflammatory effects that result in vascular damage due to improved cross talk between leukocytes and blood vessels (118). More specifically, stimulation of the vascular adhesion molecules ICAM-1 and VCAM-1 produced by ECs results in a vast improvement in leukocyte vascular adhering ability (48). Similarly, subintimal monocyte migration in atherosclerosis development is mediated by adhesion molecules (16). IS upregulates the expression of ICAM-1 and MCP-1 via ROS-induced activation of NF-κB in HUVECs (150). IS reduces vascular relaxation due to a loss of ECs and upregulation of ICAM-1/VCAM-1 expression (140).

Possible mechanisms to explain this effect include the following: 1) upregulated expression of E-selectin and subsequent activation of JNK- and NF-κB-dependent signaling pathways, which together enhance leukocyte-endothelium interactions (57); 2) increased NADPH oxidase-derived ROS through activation of the MAPK/NF-κB pathway, inducing MCP-1 expression (90), which is an inflammatory cytokine responsible for promoting monocyte migration into the arterial wall (72); and 3) induced AhR activation leading to increase in the transcription of activator protein-1, which mediates and enhances IS-enhanced leukocyte-endothelium interactions (56, 132).

In summary, PBUTs accelerate CRS via various mechanisms causing endothelial dysfunction. These include local inflammation and oxidative stress, resulting in decreased proliferation and increased senescence, disturbing the balance between injury and repair of the endothelium, which leads to artery remodeling and atherogenesis.

Other effects and mechanisms.

cytokine production and thrombosis.

IS independently associated with elevated levels of a series of inflammatory markers in patients of end-stage renal disease (ESRD). These include serum IL-6, TNF-α, and interferon (IFN)-γ (124). A link exists between increased serum levels of IL-6 and IS in patients undergoing peritoneal dialysis (69). In both HUVECs and HASMCs, IS stimulates the OAT3/AhR/NF-κB pathway, increasing IL-6 expression (1) and subsequent atherosclerosis development (41). TFs play various roles in vascular disease progression and are regulated by several signaling pathways, such as p38 MAPK (154), ERK (93), and Akt (34), with subsequent activation of the transcription factors NF-κB or EGR-1. IS increases TFs in HUVECs by AhR activation, evoking a “dioxin-like” effect (42), inducing thrombosis (21) by improving TF stability (138) and impairing its ubiquitination (21). IS also skews monocyte differentiation toward low-inflammatory, profibrotic macrophages, which contributes to sustained chronic inflammation and maladaptive vascular remodeling (11).

In addition to IS, another PBUT, p-CS, elicits proinflammatory effects by stimulating free radical production in human leucocytes (131). p-Cresol, the precursor of p-CS, mediates MCP-1 production in VSMCs, most likely by activating the NF-κB p65 pathway (88).

other effects.

The effecys of PBUTs on the vasculature are not only observed in vitro but also in vivo. IS-treated Dahl salt-sensitive hypertensive rats exhibit increased vessel wall thickness and vascular calcification in the arcuate aorta. This phenomenon was attributed to increased expression of osteoblast-specific proteins including Cbfal, ALP, and osteocalcin (2). Similarly, IS induces vascular calcification by inhibiting secreted Klotho (112) and fetuin-A (130) with prominent features of its calcification-inhibitory capacity. Low serum fetuin-A levels have also been linked with vascular calcification and cardiovascular mortality in patients undergoing hemodialysis (62) and peritoneal dialysis (156). A recent study (115) found that IS suppressed hepatic fetuin-A expression by activating AhR. In addition, IS induces junctional dispersal of bovine pulmonary artery ECs via the superoxide anion-MEK-ERK-myosin light chain (MLC) kinase (MLCK)-MLC signaling pathway (116). This results in EC cytoskeleton remodeling and accompanied impairment of the vascular bed (24, 70), a process that is also associated with atherosclerosis development.

p-CS contributes to endothelial dysfunction in hemodialysis patients by increasing concentrations of EMPs, which is possible via Rho kinase-mediating pathways (94) and impairment of the endothelial NO transduction pathway (17). In addition, IS, p-CS, and p-CG induced unusual blood flow patterns resulting from vascular leakage (118), leading to possible decreases in organ perfusion. p-CS also induces Rho kinase activation in VSMCs, resulting in a vasoconstrictive effect by inducing inward eutrophic vascular remodeling (44). Furthermore, PBUTs can cause abnormal glucose metabolism and affect blood glucose levels by promoting insulin resistance through the induction of a defect in the insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Similarly, p-CS has also been shown to disrupt the insulin pathway in vivo and in vitro by activating ERK1/2 kinase (68). IS increases the serum concentration of AGEs (76), which are involved in the pathogenesis of CVD. Finally, patients with acute kidney injury or patients with kidney transplantation develop elevated IS (163) or p-CS levels (75) that directly impair endothelial progenitor cells through a NO-dependent mechanism, resulting in subsequent neovascularization impairment.

Potential Therapeutic Strategies

Based on current knowledge, possible therapeutic interventions to ameliorate the detrimental effects of PBUTs on vasculature include the following: reducing absorption of their precursors from the gut, suppressing cellular uptake, and blocking signaling pathways by which PBUTs exert their pathological effects (e.g., p38 MAPK, ERK, PRR, and NF-κB).

Reducing the generation or absorption of PBUTs.

The precursors of IS and p-CS are indole and p-cresol, respectively. Indole and p-cresol are metabolized products of constituents of dietary proteins, including tryptophan, tyrosine, and phenylalanine, by gut bacteria (162). Administration of probiotics and prebiotics may possibly reduce indole metabolism by gut bacteria, thus reducing serum IS levels (64). Similarly, administration of symbiotic Probinul neutro reduced total serum p-cresol concentration (45) and improved endothelial reactivity (26). Alteration of the intestinal environment by lubiprostone ameliorated the progression of CKD as well as the accumulation of PBUTs in rats (96). However, a recent clinical trial (119) showed that prebiotic arabinoxylan oligosaccharides did not have any influence on microbiota-derived uremic retention solutes, including p-CS, IS, p-cresyl glucuronide, and phenylacetylglutamine. The difference between the treatment effects may be due to different characteristics of the probiotics and different patient populations studied. Further study is necessary to confirm the benefit of prebiotic therapy for CKD patients.

AST-120 is an oral charcoal adsorbent that suppresses intestinal IS absorption. Administration of AST-120 in rats reduced aortic calcification (53) and perivascular fibrosis (36) with adriamycin nephropathy. It also ameliorated endothelial dysfunction, alleviated oxidative/nitrative stress in the aorta of subtotal nephrectomized rats (106), suppressed ROS production (137), inhibited monocyte activation by inducing monocyte-driven inflammation via NAD(P)H oxidase and p38 MAPK-dependent pathways, and retarded the progression of atherosclerosis in CKD (55). Similarly, in human trials, administration of AST-120 to predialysis patients with CKD resulted in a reduction in their aortic calcification index by more than half (43). There is plenty of clinical evidence showing advantages and supporting the use of AST-120. For example, it decreased the levels of serum IS and improved malaise in a dose-dependent fashion (133), and it stunted the progression of renal dysfunction when initiated in the early stage (66). However, the Carbonaceous Oral Adsorbent's Effectiveness on Progression of Chronic Kidney Disease (CAP-KD) study showed no difference between the AST-120 plus conventional therapy group and conventional therapy group, evaluated by the primary end point (doubling of serum creatinine level, increase in serum creatinine level to 6.0 mg/dl or more, need for dialysis or transplantation, or death) (6). Additionally, recent studies also showed no benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD (134) and did not show any advantage on postponing CRF progression, mortality, and health-related quality of life in ESRD patients (20). Taken together, the benefit of AST-120 treatment is controversial, and more clinical evidence is essential to confirm its therapeutic role (167).

Suppressing transporters of PBUTs.

IS and other PBUTs are transported predominately by OAT-3 on tubular cell membranes and on VSMCs. Targeted blockages of OAT and its regulators (e.g., AhR and NF-κB p65) inhibit IS-induced proliferation, TF expression (170), and expression of proinflammation factors (1). A number of agents (e.g., riboflavin, folic acid, and aspartame) show inhibitory effects on OAT-3, but only a few have been identified to benefit IS-related cardiotoxicity. Of them, probenecid has been verified to suppress IS-induced VSMC proliferation by blocking IS uptake (169). Further research into probenecid may lead to the development of new drugs for PBUT-related vascular damage.

Antioxidant treatment.

Oxidative stress is resultant of an overproduction of free radicals and an underproduction of endogenous antioxidants (37, 149). Antioxidation therapies may be a plausible treatment for uremic patients who are under increased oxidative stress. Patients undergoing hemodialysis administered with either N-acetyl-cysteine (NAC; 600 mg bid) (145) or vitamin E (800 IU/day) (15) demonstrated significantly reduced cardiovascular events, composite CVD end points, and myocardial infarctions. Similarly, treatment with these same antioxidants resulted in significantly reduced IS oxidative stress, inducing the proliferation of HASMCs (103). The cystine-based glutathione precursor with selenomethionine, another antioxidant, was more effective than NAC in reducing oxidative stress and ameliorating cellular alterations in VSMCs (139).

Antioxidants also have been shown to inhibit ROS production, NAD(P)H oxidase activity (32), and endothelial senescence (172). Administration of ANG II receptor blocker (ARB) in ESRD patients partaking in hemodialysis results in a decreased oxidative stress index and increased plasma levels of thiol groups (61), which is an antioxidant. An inhibitor of NADPH oxidase, diphenyleneiodonium, suppressed IS-induced expression of PRR and (pro)renin in HASMCs and decreased ROS production (170).

Furthermore, folic acid therapy effectively lowered plasma homocysteine levels. High-level homocysteine is susceptible to auto-oxidation with the secondary generation of ROS and inhibits the activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase (91). It also showed the ability to decrease oxidative stress and to improve the antioxidant capacity in hemodialysis patients’ plasma (7). Likewise, supplementation of vitamin B12 decreased plasma homocysteine in ESRD patients (29), but, unfortunately, there is no evidence to show these two treatments could reduce cardiovascular complications and mortality in patients with CKD (113).

Another clinical trial involving bardoxolone methyl indicated a significant increase in the mean estimated glomerular filtration rate, compared with placebo, in patients with advanced CKD (117). This benefit resulted from the regulation of inflammation and oxidative stress, which was via the activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway (30).

In addition to medication-based treatment strategies, there are several new therapeutic strategies on hemodialysis that aim to remove PBUTs more effectively than the conventional hemodialysis. These include 1) daily hemodialysis, compared with standard 3 times/wk dialysis rhythm, can lower the mean levels of glycation-related substances and AGEs (35), which might lead to oxidative stress (98) and improve the health-related quality of life (39); 2) usage of superflux cellulose triacetate membranes was superior to low-flux membranes for clearance of most PBUTs, especially IS (28); 3) increase of the dialyzer mass transfer area coefficient and dialysate flow improved the removal of PBUTs (86); and 4) addition of activated charcoal to the dialysate showed higher efficiency in removing protein-bound solutes (95).

Blocking key signaling pathways mediated by PBUTs or other treatments.

PD-98059, a selective inhibitor of ERK, inhibits IS-induced VSMC proliferation and activation of ERK (169). Knockdown of PRR inhibits IS-induced cell proliferation and TF expression in HASMCs (170). AhR small interfering (si)RNA and NF-κB p65 siRNA inhibited IS-induced expression of IL-6 (1). Clopidogrel suppresses IS-induced generation of EMPs, known to stimulate vascular dysfunction, via the p38 MAPK signaling pathway (125). Beraprost sodium reduces the mortality of CKD rats and improves kidney function by suppressing the serum accumulation of uremic toxins such as IS. Beraprost sodium protects ECs against IS-induced injury by activating the cAMP pathway, indicating that it may be a potential treatment target for patients with CKD (168). Integrin-linked kinase (ILK) protects against EC damage induced by IS via the ILK/Akt signaling pathway (38). Rosiglitazone, known as the insulin-sensitizing drug, improved indexes of endothelial injury by decreasing NADPH oxidase 4 and NF-κB levels, preventing activation of ERK1/2 and p38 MAPK signaling pathways (22). Other potential therapies, such as traditional Chinese medicine, may be of interest for further investigation. Traditional Chinese medicine, like Tongxinluo, has been shown to prevent endothelial dysfunction by improving multiple metabolic pathways, including uremic toxins (27).

Conclusions

The dysfunction in both VSMCs and ECs is associated with the progression of CVD in CRS, and the roles of nondialyzable PBUTs in vascular pathophysiology have also been recognized. However, the mechanisms underlying the effects of PBUTs on EC and VSMC function are yet to be fully explored. Studies to date have demonstrated the detrimental vascular effects of PBUTs involving cell proliferation and senescence, vascular calcification and osteoblastic differentiation, migration, oxidative stress, as well as inflammation. Current therapeutic strategies in CRS targeting the effects of PBUTs are insufficient due to unclear pathophysiological mechanisms. Additionally, there are no known pathological functions reported for many of the PBUTs other than IS and p-CS. Other PBUTs shown in Table 1 may possess detrimental effects on both VSMCs and ECs and contribute to cardiac, vascular, and renal dysfunction. Thus, more intense investigation, including clinical research, is urgently needed to develop novel therapeutic strategies for the management of uremic vasculopathy in the setting of CRS.

GRANTS

This work was supported by National Health and Medical Research Council of Australia Program Grant 1092642 and Project Grant 1087355.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

B.H.W. conceived and designed research; J.G., L.L., and B.H.W. analyzed data; J.G., L.L., and B.H.W. interpreted results of experiments; J.G., L.L., and B.H.W. prepared figures; J.G., L.L., Y.H., K.H., I.W., L.H., A.C., P.C., H.F., Z.-m.L., and B.H.W. drafted manuscript; J.G., L.L., Y.H., K.H., I.W., L.H., Q.F., A.C., P.C., H.F., Z.-m.L., and B.H.W. edited and revised manuscript; J.G., L.L., Y.H., K.H., I.W., L.H., Q.F., A.C., P.C., H.F., Z.-m.L., and B.H.W. approved final version of manuscript.

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AUTHOR NOTES

  • * J. Guo, L. Lu, and Y. Hua contributed equally to this work.

  • Address for reprint requests and other correspondence: B. H. Wang, Centre of Cardiovascular Research and Education in Therapeutics, Dept. of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash Univ., 99 Commercial Rd., Melbourne VIC 3004, Australia (e-mail: ).