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Molecular mechanisms and physiological function of MGP. Abbreviations: MGP, matrix gla protein; Glu, glutamic acid; Gla, γ-carboxy-glutamic acid; Ser, serine; dp-ucMGP, dephosphouncarboxylated MGP; p-ucMGP, phosphorylated-uncarboxylated MGP; p-uMGP, phosphorylatedcarboxylated MGP; VSMCs, vascular smooth muscle cells.
Source publication
Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are no...
Contexts in source publication
Context 1
... molecular mechanisms of MGP and the main physiological function as inhibitor of VC are summarized in Figure 2 [12,87,[89][90][91][92][93]96]. ...
Context 2
... molecular mechanisms of MGP and the main physiological function as inhibitor of VC are summarized in Figure 2 [12,87,[89][90][91][92][93]96]. Glu, glutamic acid; Gla, γ-carboxy-glutamic acid; Ser, serine; dp-ucMGP, dephosphouncarboxylated MGP; p-ucMGP, phosphorylated-uncarboxylated MGP; p-uMGP, phosphorylatedcarboxylated MGP; VSMCs, vascular smooth muscle cells. ...
Context 3
... bone dynamics, where OC is a validated marker of bone turnover, it is also a hormone that regulates glucose metabolism [100,101]. It was demonstrated that ucOC, the active endocrine conformation, stimulates insulin secretion either directly in the pancreas or indirectly by means of increasing glucagon-like peptide-1 secretion in the small intestine, as well as release of adiponectin Figure 2. Molecular mechanisms and physiological function of MGP. ...
Citations
... The collective measurement of the inactive forms of VKDPs emerges as a rational alternative to use as biomarkers for vitamin K, due to their direct dependence on vitamin K for activation and function [33]. VKDPs provide insight into vitamin K status and implicate the consequences of its insufficiency for protein activation [34]. Initially, undercarboxylated osteocalcin (OC) was used as a biomarker, but it is mainly concentrated in bone tissue and its sensitivity is influenced by vitamin D and PTH levels (which are often disturbed in advanced CKD) [35,36]. ...
Patients with chronic kidney disease (CKD) suffer disproportionately from a high burden of cardiovascular disease, which, despite recent scientific advances, remains partly understood. Vascular calcification (VC) is the result of an ongoing process of misplaced calcium in the inner and medial layers of the arteries, which has emerged as a critical contributor to cardiovascular events in CKD. Beyond its established role in blood clotting and bone health, vitamin K appears crucial in regulating VC via vitamin K-dependent proteins (VKDPs). Among these, the matrix Gla protein (MGP) serves as both a potent inhibitor of VC and a valuable biomarker (in its inactive form) for reflecting circulating vitamin K levels. CKD patients, especially in advanced stages, often present with vitamin K deficiency due to dietary restrictions, medications, and impaired intestinal absorption in the uremic environment. Epidemiological studies confirm a strong association between vitamin K levels, inactive MGP, and increased CVD risk across CKD stages. Based on the promising results of pre-clinical data, an increasing number of clinical trials have investigated the potential benefits of vitamin K supplementation to prevent, delay, or even reverse VC, but the results have remained inconsistent.
... In comparison with hepatic VKDPs, there are many other VKDPs that are not produced in the liver (known as extra-hepatic VKDPs), the majority of them being involved in bone health and in preventing vascular calcification, which require higher amounts of vitamin K for their carboxylation [16]. Matrix Gla protein (MGP), osteocalcin (OC), growth arrest specific protein 6 (Gas6), and Gla rich protein (GRP) are some of the most studied extra-hepatic VKDPs, their carboxylation status depending on extra-hepatic vitamin K levels [17]. ...
... Short-chain fatty acids (SCFA) are carboxylic acids with up to five carbon atoms [17]. Methanolate, acetate, propionate, butyrate, and valerate are all considered SCFAs, but the majority of studies generally focus on acetate, propionate, and butyrate, as these are produced in the highest quantities in the gut. ...
Background:
The interplay between vitamin K (vitK) (as carboxylation cofactor, partially produced by the gut microbiota) and short-chain fatty acids (SCFAs), the end-product of fiber fermentation in the gut, has never been assessed in mother-newborn pairs, although newborns are considered vitK deficient and with sterile gut.
Methods:
We collected venous blood from 45 healthy mothers with uncomplicated term pregnancies and umbilical cord blood from their newborns at birth. The concentrations of total SCFAs and hepatic/extra-hepatic vitK-dependent proteins (VKDPs), as proxies of vitK status were assayed: undercarboxylated and total matrix Gla protein (ucMGP and tMGP), undercarboxylated osteocalcin (ucOC), undercarboxylated Gla-rich protein (ucGRP), and protein induced by vitK absence II (PIVKA-II).
Results:
We found significantly higher ucOC (18.6-fold), ucMGP (9.2-fold), and PIVKA-II (5.6-fold) levels in newborns, while tMGP (5.1-fold) and SCFAs (2.4-fold) were higher in mothers, and ucGRP was insignificantly modified. In mother-newborn pairs, only ucGRP (r = 0.746, p < 0.01) and SCFAs (r = 0.428, p = 0.01) levels were correlated. Conclusions: We report for the first time the presence of SCFAs in humans at birth, probably transferred through the placenta to the fetus. The increased circulating undercarboxylated VKDPSs in newborns revealed a higher vitamin K deficiency at the extrahepatic level compared to liver VKDPs.
... Cardiovascular (CV) diseases and bone disorders (next to malignancies and infections) are the most common complications in kidney transplant (KTx) recipients [1][2][3][4]. Vitamin K is considered to play a protective role in both the CV and skeletal systems [5][6][7]. The vitamin exists in two biologically active forms: K1 (PK, phylloquinone) and K2 (MK, menaquinone). ...
... There are strong suggestions that the active form of MGP is an inhibitor of vascular calcification [13,14] and may inhibit artery calcification, e.g., through binding calcium and phosphorus ions and preventing their deposition in the artery walls [15]. It was shown that an elevated level of dephosphorylated uncarboxylated MGP (dp-ucMGP, a marker of vitamin K2 insufficiency) is connected with greater arterial wall calcification in the general population as well as in patients in all stages of chronic kidney disease (CKD) [6,16]. A higher level of dp-ucMGP also correlates with the presence of atherosclerosis and coronary artery calcification in patients with advanced stages of CKD [17]. ...
... It was shown that most KTx patients have vitamin K2 insufficiency and a high level of dp-ucMGP is a risk factor for death in this population [18]. Vitamin K2 is also a cofactor for the carboxylation of osteocalcin (OC), a protein actively involved in bone remodeling [6]. The highly important role played by vitamin K2 in OC activation is evidenced by an increased risk of bone fractures in case of deficiency of this vitamin [19,20]. ...
Vitamin K, especially its K2 form, is considered to be a protective factor against developing vascular changes and bone lesions that are common complications in kidney transplant (KTx) recipients. There is a growing number of studies showing that KTx patients are at risk of vitamin K deficiency. The aim of this study was to evaluate the intake of vitamin K1 and K2 in the diet of patients in the late period after KTx. During a routine visit at one outpatient transplantation clinic in Central Europe, a diet survey questionnaire was filled in by 151 clinically stable KTx recipients and compared with medical history, anthropometric measurements and laboratory tests. Mean vitamin K1 intake was 120.9 ± 49 μg/day and vitamin K2 (MK, menaquinone) intake 28.69 ± 11.36 μg/day, including: MK-4: 25.9 ± 9.9 μg/day; MK-5: 0.1 ± 0.2 μg/day; MK-6: 0.2 ± 0.4 μg/day; MK-7: 0.2 ± 0.23 μg/day; MK-8: 1 ± 1.9 μg/day; MK-9: 0.9 ± 2.3 μg/day; and MK-10: 0.2 ± 0.5 μg/day. Our study showed that KTx recipients’ diets contained adequate amounts of vitamin K1, whereas the intake of vitamin K2 seemed insufficient.
... In the course of that reaction, carboxyl groups are added to Glu residues in proteins and transformed to Gla domains. This process transforms inactive (undercarboxylated) proteins into active (carboxylated) vitamin K-dependent proteins (cVKDPs), such as matrix Gla protein (MGP) and osteocalcin (OC) [15]. The increased circulating levels of undercarboxylated VKDPs-Glu-OC and ucMGP-reflect VK deficiency, and the measurement of these proteins is used to determine VK status [16,17]. ...
Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.
... Vascular calcification (VC) represents a dynamic event where the promoters along with inhibitors of calcification participated while currently no specific treatment is existent [5,25]. The mode of this event implicated matrix Gla protein (MGP), that possesses the maximum robustness of hampering arterial calcification that is a part of the Gla possessing proteins alias Gla-rich protein (GRP) [18,[25][26][27]29] are based on Vitamin K that is a co-factor for the transformation of glutamate into Gla [29]. ...
... Vascular calcification (VC) represents a dynamic event where the promoters along with inhibitors of calcification participated while currently no specific treatment is existent [5,25]. The mode of this event implicated matrix Gla protein (MGP), that possesses the maximum robustness of hampering arterial calcification that is a part of the Gla possessing proteins alias Gla-rich protein (GRP) [18,[25][26][27]29] are based on Vitamin K that is a co-factor for the transformation of glutamate into Gla [29]. MGP represents a small protein that possesses a molecular weight of12 kDa, that possesses 84 amino acids, 5 glutamate (Glu) as well as 3serine residues [16]. ...
... MGP liberation takes place from Chondrocytes, arterial medial vascular smooth muscle cells (VSMC), fibroblasts along with endothelial cells [25][26][27]31]. MGP results in hampering arterial calcium (Ca 2+) . ...
Vitamin K possesses numerous significant role in human health. More recently researchers have a established that healthy diet consumption possessing good fats, Vitamins, minerals, polyphenolics possesses anti-inflammatory actions can act in antiaging role. Earlier the belief was that Vitamin K acts basically as an anticoagulant, besides part in calcium homeostasis. Having reviewed the etiology in chronic kidney disease (CKD), Diabetic Kidney Disease (DKD)with those patients presenting with DKD-CKD or end stage renal Disease (ESRD), in addition to details of associated Vascular calcification, acute kidney injury here we tried to further update knowledge regarding role of Vitamin K deficit in deterioration of CKD in particular the ones associated with Vascular calcification (VC). Vitamin K plays a significant role as a co-factor in transformation of glutamate to Gla. This has a significance in hampering of VC. CKD patients both on dialysis as well as not on dialysis generally possess Vitamin K deficiency. Enhancement of uncarboxylated matrix Gla protein [MGP] (uc MGP) indirectly points to Vitamin K deficiency as well as correlated with a greater chance of generation of the cardiovascular processes. It has been pointed that greater Vitamin K consumption might cause avoidance of development of VC, besides reduction in CV risk. Thus we did a minireview utilizing the search engine pubmed, google scholar and other sutilizing the MeSH terms like DKD; CKD; Vitamin K ; Growth arrest specific protein 6 (Gas6); VC; hemodialysis (HD) patients from 2000 till date in 2022. We found s total of 65 articles with regards to CKD, Vitamin K, out of which we chose50 articles for this minireview. Despite all the research till date role of supplementation of Vitamin K with dosage, kinds still not clear that is varying from country to country as well as source VK1 or2. Still greater large RCTs are required to settle that query.
... Osteocalcin is excreted by the kidneys and we observed a higher level of osteocalcin in the CKD group compared to the control group (Silaghi et al., 2019). Accordingly, the higher levels of CTX and osteocalcin in the CKD group were likely due to the reduced kidney function and not a reflection of an elevated bone turnover. ...
Patients with chronic kidney disease (CKD) have a high risk of bone fractures. A circadian rhythmicity in turnover and mineralization of bone appears to be of importance for bone health. In CKD disturbances in the circadian rhythm of various functions has been demonstrated and indeed the circadian rhythm in the mineral metabolism is disturbed. The aim of the present study was to compare the circadian rhythm of bone turnover markers in ten patients with CKD to ten healthy controls. Bone turnover markers (C-terminal telopeptide of type I collagen, tartrate-resistant acid phosphatase 5b, N-terminal propeptide of type I procollagen, bone alkaline phosphatase and osteocalcin) were measured every third hour for 24 h. All bone turnover markers displayed a significant circadian rhythm in both groups and there were no significant differences in the rhythmicity between the two groups (no group*time interaction). As expected, due to the reduced renal clearance, the overall level of C-terminal telopeptide of type I collagen and osteocalcin was higher in CKD compared to the healthy controls. The present study suggests that disturbances in the circadian rhythm of bone turnover do not explain the metabolic bone disease and increased risk of fractures in CKD.
... Curr Osteoporos Rep sites. Thus, phosphorylation also determines the activity status: p-cMGP: active form; dp-ucMGP: inactive form; (2) OC, which is secreted exclusively in bone by osteoblasts and only a small part of it diffuses in vascular circulation, plays an essential role in the synthesis and regulation of bone matrix, and it is validated as a marker of bone turnover; (3) Gas6, a protein with a molecular weight of 75 kDa, has a characteristic function in multiple physiological activities (cellular homeostasis, cell proliferation to cell survival); (4) GRP, involved in the inhibition of articular and cardiovascular calcification and, similarly to MGP, through its ability to bind large amounts of calcium ions by the Gla residues it determines the inhibition of calcium crystal formation [5,8]. ...
... Furthermore, dp-ucMGP levels negatively associate with vitamin K status, hence decreasing with vitamin K supplementation and increasing with the use of vitamin K antagonists [27]. The levels of dp-ucMGP are markedly increased in CKD, in a stepwise way to the degree of renal failure [8]. The various circulating MGP forms, including plasma dp-ucMGP, associate with CVD outcomes and vascular calcification in the general population as well as in CKD [28]. ...
Purpose of Review
We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD).
Recent Findings
Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione.
Summary
CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.
... Vitamin K is an important element of the synthesis and action of osteocalcin, a boneforming protein [1,10,11]. Vitamin K is associated with the carboxylation of bone-related proteins, which regulate genetic transcription of osteoblastic markers as well as bone reabsorption [9][10][11]. It has been recently reported that VK2 controlled osteoblastogenesis and osteoclastogenesis by the NF-κB signal transduction pathway [2]. ...
... Vitamin K is an important element of the synthesis and action of osteocalcin, a boneforming protein [1,10,11]. Vitamin K is associated with the carboxylation of bone-related proteins, which regulate genetic transcription of osteoblastic markers as well as bone reabsorption [9][10][11]. It has been recently reported that VK2 controlled osteoblastogenesis and osteoclastogenesis by the NF-κB signal transduction pathway [2]. ...
... Low serum concentrations of VK1, high levels of undercarboxylated osteocalcin (ucOC), a marker of VK deficiency, and low VK1 an VK2 contents in the diet are associated with a higher risk of bone fractures and lower bone mineral density (BMD) [10]. Elevated serum ucOC is often found in patients with CKD with hyperparathyroidism [4,11]. However, it does not generally suggest VK deficiency [4]. ...
Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process—matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.
... Vitamin K and vitamin K-dependent proteins play essential roles in numerous processes in the human body, including roles in hemostasis, bone health, and counteracting vascular calcification [1][2][3][4]. In addition, vitamin K-deficiency is associated with increased cardiovascular risk and mortality [5][6][7]. Consequently, the potential benefits of vitamin K-supplementation are being studied in multiple patient populations [8]. For example, Nutrients 2021, 13, 3069 2 of 13 impaired vitamin K-status has been linked to increased vascular calcification, increased cardiovascular risk and mortality in patients with chronic kidney disease, and in kidney transplant recipients [9,10]. ...
... Its roles in hemostasis and bone health are well established, and its roles in counteracting vascular calcification are increasingly recognized [1][2][3][4]. Vitamin K-deficiency is strongly associated with increased cardiovascular risk and mortality, and is common in patients with kidney disease [5][6][7]30,31]. Consequently, the effects of vitamin K supplementation have been extensively studied in multiple patient populations [8]. ...
... An alternative marker of vitamin K-deficiency is ucOC. This protein is secreted by osteoblasts and undergoes post-translational vitamin K-dependent carboxylation processes similar to MGP [6,18]. However, osteocalcin also is a small protein [18], and the association with kidney function also reached statistical significance in linear regression analyses. ...
High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 ml/min/1.73m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and -0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.
... Adicionalmente, los pacientes en estadios avanzados de la ERC tratados con AVK se mantienen menos tiempo en rango terapéutico de INR en comparación con pacientes con ERC moderada o sin ERC y ello se relaciona con un aumento del riesgo tromboembólico, hemorrágico y de mortalidad 5 . Además, los agentes AVK, como acenocumarol, favorecen la calcificación vascular, ya que inhiben la ␥-carboxilación vitamina K-dependiente que precisa Matrix Gla Protein, proteína que inhibe la calcificación vascular, para su activación 6 . En pacientes con ERC, ello puede agravar el mayor riesgo cardiovascular y de calcificación vascular asociados a las alteraciones del metabolismo óseo-mineral, propios de la enfermedad, así como el riesgo de calcifilaxis 7 . ...
Resumen
Antecedentes
El cierre percutáneo de la orejuela izquierda (CPOI) se ha propuesto como una alternativa al tratamiento anticoagulante en pacientes con fibrilación auricular no valvular para disminuir el riesgo tromboembólico, evitando los riesgos de la anticoagulación. Esta opción puede ser atractiva en pacientes con fibrilación auricular no valvular y enfermedad renal crónica (ERC), ya que presentan un alto riesgo tanto tromboembólico como hemorrágico.
Objetivo
Determinar el papel pronóstico de la presencia de ERC en pacientes con fibrilación auricular sometidos a un CPOI periprocedimiento y durante el seguimiento comparado con los pacientes con función renal preservada.
Métodos
Estudio retrospectivo, observacional de muestreo consecutivo que incluyó 124 pacientes sometidos a CPOI por fibrilación auricular en un hospital universitario y se compararon los resultados según la función renal basal.
Resultados
La mediana de edad fue 75,5 años (RIQ 67,6-80), el 62,1% eran hombres, la mediana de CHA2DS2-Vasc y HASBLED era de 4 (RIQ 3-4) para ambas escalas. El 57,3% de la muestra tenía ERC. Las características basales eran similares entre ambos grupos, salvo una media de edad y un score de HASBLED superiores en los pacientes con ERC. Durante el procedimiento, no se observó ningún evento tromboembólico, de sangrado o muerte. Durante el tiempo de hospitalización y de seguimiento combinados, no hubo diferencias significativas entre grupos en la tasa anual de episodios tromboembólicos (0,97/100 pacientes-año [100PA] vs. 4,06/100PA, p = 0,092), pero si se observó una mayor tasa de sangrados (5,67/100PA vs. 13,3/100PA, p = 0,033), y de mortalidad (6,50/100PA vs. 17,2/100PA, p = 0,009) en el grupo de ERC, con una odds ratio para mortalidad de 2,711 (IC95% 1,96-6,95). En el análisis multivariante, el FGe preservado se asoció independientemente con una menor mortalidad.
Conclusiones
El CPOI es una alternativa válida a la anticoagulación oral en pacientes con ERC y fibrilación auricular, con una baja tasa de eventos peri- y posprocedimiento. No obstante, los pacientes con ERC presentan mayor riesgo de sangrado y de mortalidad durante el seguimiento. Aunque estas mayores tasas no están necesariamente relacionadas con el procedimiento.
