scholarly journals Uremic Toxins and Vascular Calcification–Missing the Forest for All the Trees

Toxins ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 624 ◽  
Author(s):  
Nikolas Rapp ◽  
Pieter Evenepoel ◽  
Peter Stenvinkel ◽  
Leon Schurgers
Keyword(s):  
Vascular Calcification ◽  
Vascular System ◽  
State Of The Art ◽  
Cardiorenal Syndrome ◽  
Uremic Toxins ◽  
Biological Mechanisms ◽  
Cardiovascular Morbidity And Mortality ◽  
Experimental Protocols ◽  
Reduced Kidney Function

The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification.

scholarly journals Inhibition of Gastrin-Releasing Peptide Attenuates Phosphate-Induced Vascular Calcification

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 737 ◽  
Author(s):  
Hyun-Joo Park ◽  
Yeon Kim ◽  
Mi-Kyoung Kim ◽  
Jae Joon Hwang ◽  
Hyung Joon Kim ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Vascular System ◽  
Ex Vivo ◽  
Calcium Deposition ◽  
Gastrin Releasing Peptide ◽  
Cardiovascular Morbidity And Mortality ◽  
Potential Strategy ◽  
Grp Receptor

Vascular calcification is the pathological deposition of calcium/phosphate in the vascular system and is closely associated with cardiovascular morbidity and mortality. Here, we investigated the role of gastrin-releasing peptide (GRP) in phosphate-induced vascular calcification and its potential regulatory mechanism. We found that the silencing of GRP gene and treatment with the GRP receptor antagonist, RC-3095, attenuated the inorganic phosphate-induced calcification of vascular smooth muscle cells (VSMCs). This attenuation was caused by inhibiting phenotype change, apoptosis and matrix vesicle release in VSMCs. Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification.

scholarly journals The Dual Role of Vitamin K2 in “Bone-Vascular Crosstalk”: Opposite Effects on Bone Loss and Vascular Calcification

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1222
Author(s):  
Domitilla Mandatori ◽  
Letizia Pelusi ◽  
Valeria Schiavone ◽  
Caterina Pipino ◽  
Natalia Di Pietro ◽  
...  
Keyword(s):  
Bone Loss ◽  
Vascular Calcification ◽  
Vascular System ◽  
The Elderly ◽  
Food Supplement ◽  
Vitamin K2 ◽  
Bioactive Molecules ◽  
Calcium Deposition ◽  
Age Related

Osteoporosis (OP) and vascular calcification (VC) represent relevant health problems that frequently coexist in the elderly population. Traditionally, they have been considered independent processes, and mainly age-related. However, an increasing number of studies have reported their possible direct correlation, commonly defined as “bone-vascular crosstalk”. Vitamin K2 (VitK2), a family of several natural isoforms also known as menaquinones (MK), has recently received particular attention for its role in maintaining calcium homeostasis. In particular, VitK2 deficiency seems to be responsible of the so-called “calcium paradox” phenomenon, characterized by low calcium deposition in the bone and its accumulation in the vessel wall. Since these events may have important clinical consequences, and the role of VitK2 in bone-vascular crosstalk has only partially been explained, this review focuses on its effects on the bone and vascular system by providing a more recent literature update. Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification, thus encouraging further in-depth studies to achieve its use as a dietary food supplement.

Abstract 1680: Notch Signaling Directly Targets Msx2: Possible Role of Notch Signaling in Osteogenic Conversion of Vascular Smooth Muscle Cells and Vascular Calcification

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takehisa Shimizu ◽  
Toru Tanaka ◽  
Tatsuya Iso ◽  
Masahiko Kurabayashi
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Notch Signaling ◽  
Vascular Calcification ◽  
Transcriptional Activity ◽  
Muscle Cells ◽  
Matrix Mineralization ◽  
Cardiovascular Morbidity And Mortality ◽  
Notch Ligands

Vascular calcification is a prominent feature of atherosclerosis and closely correlated with cardiovascular morbidity and mortality. In this study, we hypothesize that Notch signaling plays an important role in osteogenic conversion of smooth muscle cells (SMCs) and vascular calcification. <Methods and Results> Either Notch ligand-expressing cells or overexpression of Notch intracellular domains (NICDs) induced expression of Msx2, a key regulator of osteogenic conversion, in human aortic SMCs (HASMCs). In addition, overexpression of Notch1 intracellular domain (N1-ICD) markedly upregulated alkaline phosphatase (ALP) activity and matrix mineralization of HASMCs. A knockdown experiment with a small interfering RNA confirmed that Msx2, but not Runx2/Cbfa1, another key osteogenic transcription factor, is responsible for Notch1-induced osteogenic conversion of HASMCs. Furthermore, this Notch1-Msx2 pathway was independent of bone morphogenetic protein-2 (BMP-2), an osteogenic morphogen upstream of Msx2. The transcriptional activity of the Msx2 promoter was significantly enhanced by Notch ligands stimulation, whereas it was abrogated by a specific Notch signaling inhibitor. The RBP-Jk binding element within the Msx2 promoter was critical to Notch1-induced Msx2 gene expression, and correspondingly, neither N1-ICD overexpression nor Notch ligands stimulation increase the Msx2 expression or transcriptional activity of the Msx2 promoter, respectively, in RBP-Jk-deficient fibroblasts. Immunohistochemistry of human artery specimens revealed colocalization of Notch1 and Msx2 within atherosclerotic plaques, indicating a role of Notch1-Msx2 pathway in vascular calcification in vivo. These results suggest that Notch signaling directly targets Msx2, thus accelerating osteogenic conversion of HASMCs and, as a result, a formation of vascular calcification.

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

2017 ◽  
Vol 313 (1) ◽  
pp. H1-H13 ◽  
Author(s):  
Jingbin Guo ◽  
Lu Lu ◽  
Yue Hua ◽  
Kevin Huang ◽  
Ian Wang ◽  
...  
Keyword(s):  
Vascular System ◽  
Current Knowledge ◽  
Cardiorenal Syndrome ◽  
Left Ventricular ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Contributing Factors ◽  
Clinical Observations

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.

scholarly journals Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

Toxins ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 812
Author(s):  
Chia-Ter Chao ◽  
Shih-Hua Lin
Keyword(s):  
Gastrointestinal Tract ◽  
Vascular Calcification ◽  
Vascular Inflammation ◽  
Fibroblast Growth Factor 23 ◽  
Uremic Toxins ◽  
Phosphate Binders ◽  
Beneficial Effects ◽  
Cardiovascular Morbidity And Mortality ◽  
Potential Strategy ◽  
Gastrointestinal Decontamination

Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

scholarly journals Inflammatory, Metabolic, and Genetic Mechanisms of Vascular Calcification

2014 ◽  
Vol 34 (4) ◽  
pp. 715-723 ◽  
Author(s):  
Linda L. Demer ◽  
Yin Tintut
Keyword(s):  
Recent Work ◽  
Vascular Calcification ◽  
Parallel Mechanisms ◽  
Biological Mechanisms ◽  
Regulatory Pathways ◽  
Acid Protein ◽  
Cardiovascular Morbidity And Mortality ◽  
Wide Range ◽  
Carboxyglutamic Acid ◽  
Skeletal Bone

This review centers on updating the active research area of vascular calcification. This pathology underlies substantial cardiovascular morbidity and mortality, through adverse mechanical effects on vascular compliance, vasomotion, and, most likely, plaque stability. Biomineralization is a complex, regulated process occurring widely throughout nature. Decades ago, its presence in the vasculature was considered a mere curiosity and an unregulated, dystrophic process that does not involve biological mechanisms. Although it remains controversial whether the process has any adaptive value or past evolutionary advantage, substantial advances have been made in understanding the biological mechanisms driving the process. Different types of calcific vasculopathy, such as inflammatory versus metabolic, have parallel mechanisms in skeletal bone calcification, such as intramembranous and endochondral ossification. Recent work has identified important regulatory roles for inflammation, oxidized lipids, elastin, alkaline phosphatase, osteoprogenitor cells, matrix γ-carboxyglutamic acid protein, transglutaminase, osteoclastic regulatory factors, phosphate regulatory hormones and receptors, apoptosis, prelamin A, autophagy, and microvesicles or microparticles similar to the matrix vesicles of skeletal bone. Recent work has uncovered fascinating interactions between matrix γ-carboxyglutamic acid protein, vitamin K, warfarin, and transport proteins. And, lastly, recent breakthroughs in inherited forms of calcific vasculopathy have identified the genes responsible as well as an unexpected overlap of phenotypes. Until recently, vascular calcification was considered a purely degenerative, unregulated process. Since then, investigative groups around the world have identified a wide range of causative mechanisms and regulatory pathways, and some of the recent developments are highlighted in this review.

scholarly journals Vascular Calcification in Chronic Kidney Disease: The Role of Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Kerstin Benz ◽  
Karl-Friedrich Hilgers ◽  
Christoph Daniel ◽  
Kerstin Amann
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Risk Groups ◽  
Cardiovascular Complications ◽  
Atherosclerotic Plaques ◽  
Cardiovascular Morbidity And Mortality ◽  
Functional Factors ◽  
Age And Sex

Cardiovascular complications are extremely frequent in patients with chronic kidney disease (CKD) and death from cardiac causes is the most common cause of death in this particular population. Cardiovascular disease is approximately 3 times more frequent in patients with CKD than in other known cardiovascular risk groups and cardiovascular mortality is approximately 10-fold more frequent in patients on dialysis compared to the age- and sex-matched segments of the nonrenal population. Among other structural and functional factors advanced calcification of atherosclerotic plaques as well as of the arterial and venous media has been described as potentially relevant for this high cardiovascular morbidity and mortality. One potential explanation for this exceedingly high vascular calcification in animal models as well as in patients with CKD increased systemic and most importantly local (micro)inflammation that has been shown to favor the development of calcifying particles by multiple ways. Of note, local vascular upregulation of proinflammatory and proosteogenic molecules is already present at early stages of CKD and may thus be operative for vascular calcification. In addition, increased expression of costimulatory molecules and mast cells has also been documented in patients with CKD pointing to a more inflammatory and potentially less stable phenotype of coronary atherosclerotic plaques in CKD.

Vascular calcification: the role of microRNAs

2017 ◽  
Vol 8 (2) ◽  
pp. 119-123 ◽  
Author(s):  
Stelina Alkagiet ◽  
Konstantinos Tziomalos
Keyword(s):  
Vascular Calcification ◽  
Vascular Wall ◽  
Protective Role ◽  
Left Ventricular ◽  
Coronary Perfusion ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Phosphate Salts

AbstractVascular calcification represents the deposition of calcium phosphate salts in the tunica media of the vascular wall. It occurs during aging but is accelerated and pronounced in patients with diabetes mellitus, chronic kidney disease (CKD) and established cardiovascular disease. Due to the loss of elasticity of the vessel wall, vascular calcification might result in left ventricular hypertrophy and compromise coronary perfusion. Accordingly, several studies showed that vascular calcification is associated with increased risk for cardiovascular morbidity and mortality. Accumulating data suggest that microRNAs (miRs) play an important role in vascular calcification. A variety of miRs have been implicated in the development of vascular calcification, whereas others appear to play a protective role. Accordingly, miRs might represent promising targets for the prevention of vascular calcification and its adverse cardiovascular sequelae. However, given the complexity of regulation of this process and the multitude of miRs involved, more research is needed to identify the optimal candidate miRs for targeting.

scholarly journals Role of Uremic Toxins in Early Vascular Ageing and Calcification

Toxins ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 26
Author(s):  
Nikolaos C. Kyriakidis ◽  
Gabriela Cobo ◽  
Lu Dai ◽  
Bengt Lindholm ◽  
Peter Stenvinkel
Keyword(s):  
Clinical Impact ◽  
Uremic Toxins ◽  
Biological Functions ◽  
Aberrant Expression ◽  
Advanced Chronic Kidney Disease ◽  
Vascular Ageing ◽  
Biologic Effects ◽  
Reduced Kidney Function ◽  
Harmful Effects

In patients with advanced chronic kidney disease (CKD), the accumulation of uremic toxins, caused by a combination of decreased excretion secondary to reduced kidney function and increased generation secondary to aberrant expression of metabolite genes, interferes with different biological functions of cells and organs, contributing to a state of chronic inflammation and other adverse biologic effects that may cause tissue damage. Several uremic toxins have been implicated in severe vascular smooth muscle cells (VSMCs) changes and other alterations leading to vascular calcification (VC) and early vascular ageing (EVA). The above mentioned are predominant clinical features of patients with CKD, contributing to their exceptionally high cardiovascular mortality. Herein, we present an update on pathophysiological processes and mediators underlying VC and EVA induced by uremic toxins. Moreover, we discuss their clinical impact, and possible therapeutic targets aiming at preventing or ameliorating the harmful effects of uremic toxins on the vasculature.

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