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Dr. Juan R. Muñoz-Castañeda
Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Nephrology Department. Hospital Universitario Reina Sofía de Córdoba, Spain

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Research Keywords & Expertise

0 Chronic Kidney Disease
0 mineral metabolism
0 Wnt/β-catenin
0 renal osteodystrophy
0 VASCULAR CALCIFICATION

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Wnt/β-catenin
Chronic Kidney Disease
VASCULAR CALCIFICATION
Klotho
mineral metabolism
Hyperphosphatemia
Hypomagnesemia

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Original article
Published: 18 April 2021 in European Journal of Clinical Investigation
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Background Inflammation is a common feature in chronic kidney disease (CKD) that appears specifically associated with cardiovascular derangements in CKD patients. Observational studies have revealed a link between low Mg levels and inflammation. In this study, we hypothesize that Mg might have a modulatory effect on the inflammation induced under the uraemic milieu. Methods In vivo studies were performed in a 5/6 nephrectomized rat model of CKD. Furthermore, a possible direct effect of Mg was addressed through in vitro studies with vascular smooth muscle cells (VSMCs). Results Uraemic rats fed a normal (0.1%) Mg diet showed a systemic inflammatory response evidenced by the elevation in plasma of the pro‐inflammatory cytokines TNF‐α, IL‐1β and IL‐6, and GPx activity, a marker of oxidative stress. Importantly, an increased expression of these cytokines in the aortic tissue was also observed. In contrast, a dietary Mg supplementation (0.6%) greatly prevented the oxidative stress and the pro‐inflammatory response. In vitro, in VSMCs cultured in a pro‐inflammatory high phosphate medium, incubation with Mg 1.6 mM inhibited the increase in the production of ROS, the rise in the expression of TNF‐α, IL‐1β, IL‐6 and IL‐8 and the activation of NF‐κB signalling that was observed in cells incubated with a normal (0.8 mM) Mg. Conclusion Mg supplementation reduced inflammation associated with CKD, exerting a direct effect on vascular cells. These findings support a possible beneficial effect of Mg supplementation along the clinical management of CKD patients.

ACS Style

Rodrigo López‐Baltanás; Maria Encarnación Rodríguez‐Ortiz; Antonio Canalejo; Juan M. Díaz‐Tocados; Carmen Herencia; Fernando Leiva‐Cepas; José D. Torres‐Peña; Ana Ortíz‐Morales; Juan Rafael Muñoz‐Castañeda; Mariano Rodríguez; Yolanda Almadén. Magnesium supplementation reduces inflammation in rats with induced chronic kidney disease. European Journal of Clinical Investigation 2021, e13561 .

AMA Style

Rodrigo López‐Baltanás, Maria Encarnación Rodríguez‐Ortiz, Antonio Canalejo, Juan M. Díaz‐Tocados, Carmen Herencia, Fernando Leiva‐Cepas, José D. Torres‐Peña, Ana Ortíz‐Morales, Juan Rafael Muñoz‐Castañeda, Mariano Rodríguez, Yolanda Almadén. Magnesium supplementation reduces inflammation in rats with induced chronic kidney disease. European Journal of Clinical Investigation. 2021; ():e13561.

Chicago/Turabian Style

Rodrigo López‐Baltanás; Maria Encarnación Rodríguez‐Ortiz; Antonio Canalejo; Juan M. Díaz‐Tocados; Carmen Herencia; Fernando Leiva‐Cepas; José D. Torres‐Peña; Ana Ortíz‐Morales; Juan Rafael Muñoz‐Castañeda; Mariano Rodríguez; Yolanda Almadén. 2021. "Magnesium supplementation reduces inflammation in rats with induced chronic kidney disease." European Journal of Clinical Investigation , no. : e13561.

Journal article
Published: 20 January 2021 in Nutrients
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In chronic kidney disease (CKD) patients, it would be desirable to reduce the intake of inorganic phosphate (P) rather than limit the intake of P contained in proteins. Urinary excretion of P should reflect intestinal absorption of P(inorganic plus protein-derived). The aim of the present study is to determine whether the ratio of urinary P to urinary urea nitrogen (P/UUN ratio) helps identify patients with a high intake of inorganic P.A cross-sectional study was performed in 71 patients affected by metabolic syndrome with CKD (stages 2–3) with normal serum P concentration. A 3-day dietary survey was performed to estimate the average daily amount and the source of P ingested. The daily intake ofPwas1086.5 ± 361.3mg/day; 64% contained in animal proteins, 22% in vegetable proteins, and 14% as inorganic P. The total amount of P ingested did not correlate with daily phosphaturia, but it did correlate with the P/UUN ratio (p < 0.018). Patients with the highest tertile of the P/UUN ratio >71.1 mg/g presented more abundant inorganic P intake (p < 0.038).The P/UUN ratio is suggested to be a marker of inorganic P intake. This finding might be useful in clinical practices to identify the source of dietary P and to make personalized dietary recommendations directed to reduce inorganic P intake.

ACS Style

María Pendón-Ruiz de Mier; Noemí Vergara; Cristian Rodelo-Haad; María López-Zamorano; Cristina Membrives-González; Rodrigo López-Baltanás; Juan Muñoz-Castañeda; Francisco Caravaca; Alejandro Martín-Malo; Arnold Felsenfeld; Eugenio De la Torre; Sagrario Soriano; Rafael Santamaría; Mariano Rodríguez. Assessment of Inorganic Phosphate Intake by the Measurement of the Phosphate/Urea Nitrogen Ratio in Urine. Nutrients 2021, 13, 292 .

AMA Style

María Pendón-Ruiz de Mier, Noemí Vergara, Cristian Rodelo-Haad, María López-Zamorano, Cristina Membrives-González, Rodrigo López-Baltanás, Juan Muñoz-Castañeda, Francisco Caravaca, Alejandro Martín-Malo, Arnold Felsenfeld, Eugenio De la Torre, Sagrario Soriano, Rafael Santamaría, Mariano Rodríguez. Assessment of Inorganic Phosphate Intake by the Measurement of the Phosphate/Urea Nitrogen Ratio in Urine. Nutrients. 2021; 13 (2):292.

Chicago/Turabian Style

María Pendón-Ruiz de Mier; Noemí Vergara; Cristian Rodelo-Haad; María López-Zamorano; Cristina Membrives-González; Rodrigo López-Baltanás; Juan Muñoz-Castañeda; Francisco Caravaca; Alejandro Martín-Malo; Arnold Felsenfeld; Eugenio De la Torre; Sagrario Soriano; Rafael Santamaría; Mariano Rodríguez. 2021. "Assessment of Inorganic Phosphate Intake by the Measurement of the Phosphate/Urea Nitrogen Ratio in Urine." Nutrients 13, no. 2: 292.

Review
Published: 12 November 2020 in Frontiers in Cell and Developmental Biology
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Some of the critical mechanisms that mediate chronic kidney disease (CKD) progression are associated with vascular calcifications, disbalance of mineral metabolism, increased oxidative and metabolic stress, inflammation, coagulation abnormalities, endothelial dysfunction, or accumulation of uremic toxins. Also, it is widely accepted that pathologies with a strong influence in CKD progression are diabetes, hypertension, and cardiovascular disease (CVD). A disbalance in magnesium (Mg) homeostasis, more specifically hypomagnesemia, is associated with the development and progression of the comorbidities mentioned above, and some mechanisms might explain why low serum Mg is associated with negative clinical outcomes such as major adverse cardiovascular and renal events. Furthermore, it is likely that hypomagnesemia causes the release of inflammatory cytokines and C-reactive protein and promotes insulin resistance. Animal models have shown that Mg supplementation reverses vascular calcifications; thus, clinicians have focused on the potential benefits that Mg supplementation may have in humans. Recent evidence suggests that Mg reduces coronary artery calcifications and facilitates peripheral vasodilation. Mg may reduce vascular calcification by direct inhibition of the Wnt/β-catenin signaling pathway. Furthermore, Mg deficiency worsens kidney injury induced by an increased tubular load of phosphate. One important consequence of excessive tubular load of phosphate is the reduction of renal tubule expression of α-Klotho in moderate CKD. Low Mg levels worsen the reduction of Klotho induced by the tubular load of phosphate. Evidence to support clinical translation is yet insufficient, and more clinical studies are required to claim enough evidence for decision-making in daily practice. Meanwhile, it seems reasonable to prevent and treat Mg deficiency. This review aims to summarize the current understanding of Mg homeostasis, the potential mechanisms that may mediate the effect of Mg deficiency on CKD progression, CVD, and mortality.

ACS Style

Cristian Rodelo-Haad; M. Victoria Pendón-Ruiz De Mier; Juan Miguel Díaz-Tocados; Alejandro Martin-Malo; Rafael Santamaria; Juan Rafael Muñoz-Castañeda; Mariano Rodríguez. The Role of Disturbed Mg Homeostasis in Chronic Kidney Disease Comorbidities. Frontiers in Cell and Developmental Biology 2020, 8, 1 .

AMA Style

Cristian Rodelo-Haad, M. Victoria Pendón-Ruiz De Mier, Juan Miguel Díaz-Tocados, Alejandro Martin-Malo, Rafael Santamaria, Juan Rafael Muñoz-Castañeda, Mariano Rodríguez. The Role of Disturbed Mg Homeostasis in Chronic Kidney Disease Comorbidities. Frontiers in Cell and Developmental Biology. 2020; 8 ():1.

Chicago/Turabian Style

Cristian Rodelo-Haad; M. Victoria Pendón-Ruiz De Mier; Juan Miguel Díaz-Tocados; Alejandro Martin-Malo; Rafael Santamaria; Juan Rafael Muñoz-Castañeda; Mariano Rodríguez. 2020. "The Role of Disturbed Mg Homeostasis in Chronic Kidney Disease Comorbidities." Frontiers in Cell and Developmental Biology 8, no. : 1.

Review
Published: 16 March 2020 in Toxins
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Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications.

ACS Style

Juan Rafael Muñoz-Castañeda; Cristian Rodelo-Haad; Maria Victoria Pendon-Ruiz De Mier; Alejandro Martin-Malo; Rafael Santamaria; Mariano Rodriguez. Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease. Toxins 2020, 12, 185 .

AMA Style

Juan Rafael Muñoz-Castañeda, Cristian Rodelo-Haad, Maria Victoria Pendon-Ruiz De Mier, Alejandro Martin-Malo, Rafael Santamaria, Mariano Rodriguez. Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease. Toxins. 2020; 12 (3):185.

Chicago/Turabian Style

Juan Rafael Muñoz-Castañeda; Cristian Rodelo-Haad; Maria Victoria Pendon-Ruiz De Mier; Alejandro Martin-Malo; Rafael Santamaria; Mariano Rodriguez. 2020. "Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease." Toxins 12, no. 3: 185.

Journal article
Published: 04 February 2020 in Scientific Reports
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To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.

ACS Style

Angela Vidal; Rafael Rios; Carmen Pineda; Ignacio Lopez; Juan R. Muñoz-Castañeda; Mariano Rodriguez; Escolastico Aguilera-Tejero; Ana I. Raya. Direct regulation of fibroblast growth factor 23 by energy intake through mTOR. Scientific Reports 2020, 10, 1795 -10.

AMA Style

Angela Vidal, Rafael Rios, Carmen Pineda, Ignacio Lopez, Juan R. Muñoz-Castañeda, Mariano Rodriguez, Escolastico Aguilera-Tejero, Ana I. Raya. Direct regulation of fibroblast growth factor 23 by energy intake through mTOR. Scientific Reports. 2020; 10 (1):1795-10.

Chicago/Turabian Style

Angela Vidal; Rafael Rios; Carmen Pineda; Ignacio Lopez; Juan R. Muñoz-Castañeda; Mariano Rodriguez; Escolastico Aguilera-Tejero; Ana I. Raya. 2020. "Direct regulation of fibroblast growth factor 23 by energy intake through mTOR." Scientific Reports 10, no. 1: 1795-10.

Research article
Published: 03 January 2020 in Clinical Science
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Fibroblast growth factor 23 (FGF23) increases phosphorus excretion and decreases calcitriol (1,25(OH)2D) levels. FGF23 increases from early stages of renal failure. We evaluated whether strict control of phosphorus intake in renal failure prevents the increase in FGF23 and to what extent inflammation impairs regulation of FGF23. The study was performed in 5/6 nephrectomized (Nx) Wistar rats fed diets containing 0.2–1.2% phosphorus for 3 or 15 days. FGF23 levels significantly increased in all Nx groups in the short-term (3-day) experiment. However, at 15 days, FGF23 increased in all Nx rats except in those fed 0.2% phosphorus. In a second experiment, Nx rats fed low phosphorus diets (0.2 and 0.4%) for 15 days received daily intraperitoneal lipopolysaccharide (LPS) injections to induce inflammation. In these rats, FGF23 increased despite the low phosphorus diets. Thus, higher FGF23 levels were needed to maintain phosphaturia and normal serum phosphorus values. Renal Klotho expression was preserved in Nx rats on a 0.2% phosphorus diet, reduced on a 0.4% phosphorus diet, and markedly reduced in Nx rats receiving LPS. In ex vivo experiments, high phosphorus and LPS increased nuclear β-catenin and p65-NFκB and decreased Klotho. Inhibition of inflammation and Wnt signaling activation resulted in decreased FGF23 levels and increased renal Klotho. In conclusion, strict control of phosphorus intake prevented the increase in FGF23 in renal failure, whereas inflammation independently increased FGF23 values. Decreased Klotho may explain the renal resistance to FGF23 in inflammation. These effects are likely mediated by the activation of NFkB and Wnt/β-catenin signaling.

ACS Style

Maria E. Rodríguez-Ortiz; Juan M. Díaz-Tocados; Juan R. Muñoz-Castañeda; Carmen Herencia; Carmen Pineda; Julio Martínez; Addy Montes De Oca; Rodrigo López-Baltanás; Juan Francisco Alcala-Diaz; Alberto Ortiz; Escolástico Aguilera-Tejero; Arnold Felsenfeld; Mariano Rodríguez; Yolanda Almadén. Inflammation both increases and causes resistance to FGF23 in normal and uremic rats. Clinical Science 2020, 134, 15 -32.

AMA Style

Maria E. Rodríguez-Ortiz, Juan M. Díaz-Tocados, Juan R. Muñoz-Castañeda, Carmen Herencia, Carmen Pineda, Julio Martínez, Addy Montes De Oca, Rodrigo López-Baltanás, Juan Francisco Alcala-Diaz, Alberto Ortiz, Escolástico Aguilera-Tejero, Arnold Felsenfeld, Mariano Rodríguez, Yolanda Almadén. Inflammation both increases and causes resistance to FGF23 in normal and uremic rats. Clinical Science. 2020; 134 (1):15-32.

Chicago/Turabian Style

Maria E. Rodríguez-Ortiz; Juan M. Díaz-Tocados; Juan R. Muñoz-Castañeda; Carmen Herencia; Carmen Pineda; Julio Martínez; Addy Montes De Oca; Rodrigo López-Baltanás; Juan Francisco Alcala-Diaz; Alberto Ortiz; Escolástico Aguilera-Tejero; Arnold Felsenfeld; Mariano Rodríguez; Yolanda Almadén. 2020. "Inflammation both increases and causes resistance to FGF23 in normal and uremic rats." Clinical Science 134, no. 1: 15-32.

Journal article
Published: 11 December 2019 in Clinica Chimica Acta
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Chronic kidney disease (CKD) is associated with a wide number of abnormalities in mineral metabolism. Often, these alterations are the leading players in the development of comorbidities associated with CKD, which are risk factors of mortality. In this context, mineral and bone disorder associated with CKD (CKD-MBD) are highlighted, connecting bone, renal, and cardiovascular disorders. Many studies have been led to propose strategies to avoid, reduce, or slow down CKD-MBD progression using different compositions of metallic elements-based P binders such as aluminum, magnesium, or calcium. Magnesium, the aim of this review, has been used by nephrologists to treat CKD-MBD with a variable acceptation due mainly to different results on bone homeostasis. Nowadays, we have new evidence about the efficacy of magnesium supplementation on vascular calcification, renal function, and bone disorders, suggesting potential beneficial effects of Magnesium in the management of CKD-MBD.

ACS Style

M.V. Pendón-Ruiz de Mier; Cristian Rodelo-Haad; J.M. Díaz-Tocados; J.R. Muñoz-Castañeda; M. Rodríguez. Magnesium: An old player revisited in the context of CKD-MBD. Clinica Chimica Acta 2019, 501, 53 -59.

AMA Style

M.V. Pendón-Ruiz de Mier, Cristian Rodelo-Haad, J.M. Díaz-Tocados, J.R. Muñoz-Castañeda, M. Rodríguez. Magnesium: An old player revisited in the context of CKD-MBD. Clinica Chimica Acta. 2019; 501 ():53-59.

Chicago/Turabian Style

M.V. Pendón-Ruiz de Mier; Cristian Rodelo-Haad; J.M. Díaz-Tocados; J.R. Muñoz-Castañeda; M. Rodríguez. 2019. "Magnesium: An old player revisited in the context of CKD-MBD." Clinica Chimica Acta 501, no. : 53-59.

Review
Published: 22 March 2019 in Toxins
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Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future.

ACS Style

Cristian Rodelo-Haad; Rafael Santamaria; Juan R. Muñoz-Castañeda; M. Victoria Pendón-Ruiz De Mier; Alejandro Martin-Malo; Mariano Rodriguez. FGF23, Biomarker or Target? Toxins 2019, 11, 175 .

AMA Style

Cristian Rodelo-Haad, Rafael Santamaria, Juan R. Muñoz-Castañeda, M. Victoria Pendón-Ruiz De Mier, Alejandro Martin-Malo, Mariano Rodriguez. FGF23, Biomarker or Target? Toxins. 2019; 11 (3):175.

Chicago/Turabian Style

Cristian Rodelo-Haad; Rafael Santamaria; Juan R. Muñoz-Castañeda; M. Victoria Pendón-Ruiz De Mier; Alejandro Martin-Malo; Mariano Rodriguez. 2019. "FGF23, Biomarker or Target?" Toxins 11, no. 3: 175.

Journal article
Published: 12 September 2018 in Scientific Reports
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In chronic kidney disease (CKD), high serum phosphate concentration is associated with cardiovascular disease and deterioration in renal function. In early CKD, the serum phosphate concentration is normal due to increased fractional excretion of phosphate. Our premise was that high phosphate intake even in patients with early CKD would result in an excessive load of phosphate causing tubular injury and accelerating renal function deterioration. In CKD 2-3 patients, we evaluated whether increased phosphaturia accelerates CKD progression. To have a uniform group of patients with early CKD, 95 patients with metabolic syndrome without overt proteinuria were followed for 2.7 ± 1.6 years. The median decline in eGFR was 0.50 ml/min/1.73 m2/year. Patients with a more rapid decrease in eGFR had greater phosphaturia. Moreover, the rate of decrease in eGFR inversely correlated with the degree of phosphaturia. Additionally, phosphaturia independently predicted renal function deterioration. In heminephrectomized rats, a high phosphate diet increased phosphaturia resulting in renal tubular damage associated with inflammation, oxidative stress and low klotho expression. Moreover, in rats with hyperphosphatemia and metabolic syndrome antioxidant treatment resulted in attenuation of renal lesions. In HEK-293 cells, high phosphate promoted oxidative stress while melatonin administration reduced ROS generation. Our findings suggest that phosphate loading in early CKD, results in renal damage and a more rapid decrease in renal function due to renal tubular injury.

ACS Style

Rafael Santamaría; Juan M. Díaz-Tocados; M. Victoria Pendón-Ruiz De Mier; Ana Robles; M. Dolores Salmerón-Rodríguez; Erena Ruiz; Noemi Vergara; Escolástico Aguilera-Tejero; Ana Raya; Rosa Ortega; Arnold Felsenfeld; Juan R. Muñoz-Castañeda; Alejandro Martín-Malo; Pedro Aljama; Mariano Rodríguez. Increased Phosphaturia Accelerates The Decline in Renal Function: A Search for Mechanisms. Scientific Reports 2018, 8, 13701 .

AMA Style

Rafael Santamaría, Juan M. Díaz-Tocados, M. Victoria Pendón-Ruiz De Mier, Ana Robles, M. Dolores Salmerón-Rodríguez, Erena Ruiz, Noemi Vergara, Escolástico Aguilera-Tejero, Ana Raya, Rosa Ortega, Arnold Felsenfeld, Juan R. Muñoz-Castañeda, Alejandro Martín-Malo, Pedro Aljama, Mariano Rodríguez. Increased Phosphaturia Accelerates The Decline in Renal Function: A Search for Mechanisms. Scientific Reports. 2018; 8 (1):13701.

Chicago/Turabian Style

Rafael Santamaría; Juan M. Díaz-Tocados; M. Victoria Pendón-Ruiz De Mier; Ana Robles; M. Dolores Salmerón-Rodríguez; Erena Ruiz; Noemi Vergara; Escolástico Aguilera-Tejero; Ana Raya; Rosa Ortega; Arnold Felsenfeld; Juan R. Muñoz-Castañeda; Alejandro Martín-Malo; Pedro Aljama; Mariano Rodríguez. 2018. "Increased Phosphaturia Accelerates The Decline in Renal Function: A Search for Mechanisms." Scientific Reports 8, no. 1: 13701.

Review
Published: 27 February 2018 in International Journal of Molecular Sciences
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Patients with advanced chronic kidney disease exhibit an increase in cardiovascular mortality. Recent works have shown that low levels of magnesium are associated with increased cardiovascular and all-cause mortality in hemodialysis patients. Epidemiological studies suggest an influence of low levels of magnesium on the occurrence of cardiovascular disease, which is also observed in the normal population. Magnesium is involved in critical cellular events such as apoptosis and oxidative stress. It also participates in a number of enzymatic reactions. In animal models of uremia, dietary supplementation of magnesium reduces vascular calcifications and mortality; in vitro, an increase of magnesium concentration decreases osteogenic transdifferentiation of vascular smooth muscle cells. Therefore, it may be appropriate to evaluate whether magnesium replacement should be administered in an attempt to reduce vascular damage and mortality in the uremic population In the present manuscript, we will review the magnesium homeostasis, the involvement of magnesium in enzymatic reactions, apoptosis and oxidative stress and the clinical association between magnesium and cardiovascular disease in the general population and in the context of chronic kidney disease. We will also analyze the role of magnesium on kidney function. Finally, the experimental evidence of the beneficial effects of magnesium replacement in chronic kidney disease will be thoroughly described.

ACS Style

Juan R. Muñoz-Castañeda; María V. Pendón-Ruiz De Mier; Mariano Rodríguez; María E. Rodríguez-Ortiz. Magnesium Replacement to Protect Cardiovascular and Kidney Damage? Lack of Prospective Clinical Trials. International Journal of Molecular Sciences 2018, 19, 664 .

AMA Style

Juan R. Muñoz-Castañeda, María V. Pendón-Ruiz De Mier, Mariano Rodríguez, María E. Rodríguez-Ortiz. Magnesium Replacement to Protect Cardiovascular and Kidney Damage? Lack of Prospective Clinical Trials. International Journal of Molecular Sciences. 2018; 19 (3):664.

Chicago/Turabian Style

Juan R. Muñoz-Castañeda; María V. Pendón-Ruiz De Mier; Mariano Rodríguez; María E. Rodríguez-Ortiz. 2018. "Magnesium Replacement to Protect Cardiovascular and Kidney Damage? Lack of Prospective Clinical Trials." International Journal of Molecular Sciences 19, no. 3: 664.

Journal article
Published: 01 November 2017 in Kidney International
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Although magnesium has been shown to prevent vascular calcification in vitro, controlled in vivo studies in uremic animal models are limited. To determine whether dietary magnesium supplementation protects against the development of vascular calcification, 5/6 nephrectomized Wistar rats were fed diets with different magnesium content increasing from 0.1 to 1.1%. In one study we analyzed bone specimens from rats fed 0.1%, 0.3%, and 0.6% magnesium diets, and in another study we evaluated the effect of intraperitoneal magnesium on vascular calcification in 5/6 nephrectomized rats. The effects of magnesium on established vascular calcification were also evaluated in uremic rats fed on diets with either normal (0.1%) or moderately increased magnesium (0.6%) content. The increase in dietary magnesium resulted in a marked reduction in vascular calcification, together with improved mineral metabolism and renal function. Moderately elevated dietary magnesium (0.3%), but not high dietary magnesium (0.6%), improved bone homeostasis as compared to basal dietary magnesium (0.1%). Results of our study also suggested that the protective effect of magnesium on vascular calcification was not limited to its action as an intestinal phosphate binder since magnesium administered intraperitoneally also decreased vascular calcification. Oral magnesium supplementation also reduced blood pressure in uremic rats, and in vitro medium magnesium decreased BMP-2 and p65-NF-κB in TNF-α-treated human umbilical vein endothelial cells. Finally, in uremic rats with established vascular calcification, increasing dietary magnesium from 0.1% magnesium to 0.6% reduced the mortality rate from 52% to 28%, which was associated with reduced vascular calcification. Thus, increasing dietary magnesium reduced both vascular calcification and mortality in uremic rats.

ACS Style

Juan M. Diaz-Tocados; Alan Peralta-Ramírez; María E. Rodríguez-Ortiz; Antonio Canalejo Raya; Ignacio Lopez; Carmen Pineda; Carmen Herencia; Addy Montes de Oca; Noemi Vergara; Sonja Steppan; M. Victoria Pendon-Ruiz de Mier; Paula Buendía; Andrés Carmona; Julia Carracedo; Juan Francisco Alcala-Diaz; João Frazão; Julio Martínez; Antonio Canalejo; Arnold Felsenfeld; Mariano Rodriguez; Escolástico Aguilera-Tejero; Yolanda Almadén; Juan R. Muñoz-Castañeda. Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats. Kidney International 2017, 92, 1084 -1099.

AMA Style

Juan M. Diaz-Tocados, Alan Peralta-Ramírez, María E. Rodríguez-Ortiz, Antonio Canalejo Raya, Ignacio Lopez, Carmen Pineda, Carmen Herencia, Addy Montes de Oca, Noemi Vergara, Sonja Steppan, M. Victoria Pendon-Ruiz de Mier, Paula Buendía, Andrés Carmona, Julia Carracedo, Juan Francisco Alcala-Diaz, João Frazão, Julio Martínez, Antonio Canalejo, Arnold Felsenfeld, Mariano Rodriguez, Escolástico Aguilera-Tejero, Yolanda Almadén, Juan R. Muñoz-Castañeda. Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats. Kidney International. 2017; 92 (5):1084-1099.

Chicago/Turabian Style

Juan M. Diaz-Tocados; Alan Peralta-Ramírez; María E. Rodríguez-Ortiz; Antonio Canalejo Raya; Ignacio Lopez; Carmen Pineda; Carmen Herencia; Addy Montes de Oca; Noemi Vergara; Sonja Steppan; M. Victoria Pendon-Ruiz de Mier; Paula Buendía; Andrés Carmona; Julia Carracedo; Juan Francisco Alcala-Diaz; João Frazão; Julio Martínez; Antonio Canalejo; Arnold Felsenfeld; Mariano Rodriguez; Escolástico Aguilera-Tejero; Yolanda Almadén; Juan R. Muñoz-Castañeda. 2017. "Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats." Kidney International 92, no. 5: 1084-1099.

Journal article
Published: 19 September 2017 in The FASEB Journal
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In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)-23. Abnormal regulation of the FGFR1-Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)-1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a high-phosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti-FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β-catenin, together with a reduction in Klotho. Wnt/β-catenin inhibition with Dkk-1 prevented the P-induced down-regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β-catenin pathway.—Muñoz-Castañeda, J. R., Herencia, C., Pendón-Ruiz de Mier, M. V., Rodriguez-Ortiz, M. E., Diaz-Tocados, J. M., Vergara, N., Martínez-Moreno, J. M., Salmerón, M. D., Richards, W. G., Felsenfeld, A., Kuro-O, M., Almadén, Y., Rodríguez, M. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats.

ACS Style

Juan R. Muñoz‐Castañeda; Carmen Herencia; Maria Victoria Pendón‐Ruiz de Mier; Maria Encarnación Rodriguez‐Ortiz; Juan M. Diaz‐Tocados; Noemi Vergara; Julio M. Martínez‐Moreno; Maria Dolores Salmerón; William G. Richards; Arnold Felsenfeld; Makoto Kuro‐O; Yolanda Almadén; Mariano Rodríguez. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. The FASEB Journal 2017, 31, 3858 -3867.

AMA Style

Juan R. Muñoz‐Castañeda, Carmen Herencia, Maria Victoria Pendón‐Ruiz de Mier, Maria Encarnación Rodriguez‐Ortiz, Juan M. Diaz‐Tocados, Noemi Vergara, Julio M. Martínez‐Moreno, Maria Dolores Salmerón, William G. Richards, Arnold Felsenfeld, Makoto Kuro‐O, Yolanda Almadén, Mariano Rodríguez. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. The FASEB Journal. 2017; 31 (9):3858-3867.

Chicago/Turabian Style

Juan R. Muñoz‐Castañeda; Carmen Herencia; Maria Victoria Pendón‐Ruiz de Mier; Maria Encarnación Rodriguez‐Ortiz; Juan M. Diaz‐Tocados; Noemi Vergara; Julio M. Martínez‐Moreno; Maria Dolores Salmerón; William G. Richards; Arnold Felsenfeld; Makoto Kuro‐O; Yolanda Almadén; Mariano Rodríguez. 2017. "Differential regulation of renal Klotho and FGFR1 in normal and uremic rats." The FASEB Journal 31, no. 9: 3858-3867.

Journal article
Published: 10 August 2017 in Scientific Reports
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Mesenchymal stem cells (MSC) are osteoblasts progenitors and a variety of studies suggest that they may play an important role for the health in the field of bone regeneration. Magnesium supplementation is gaining importance as adjuvant treatment to improve osteogenesis, although the mechanisms involving this process are not well understood. The objective of this study was to investigate the effects of magnesium on MSC differentiation. Here we show that in rat bone marrow MSC, magnesium chloride increases MSC proliferation in a dose-dependent manner promoting osteogenic differentiation and mineralization. These effects are reduced by 2-APB administration, an inhibitor of magnesium channel TRPM7. Of note, magnesium supplementation did not increase the canonical Wnt/β-catenin pathway, although it promoted the activation of Notch1 signaling, which was also decreased by addition of 2-APB. Electron microscopy showed higher proliferation, organization and maturation of osteoblasts in bone decellularized scaffolds after magnesium addition. In summary, our results demonstrate that magnesium chloride enhances MSC proliferation by Notch1 signaling activation and induces osteogenic differentiation, shedding light on the understanding of the role of magnesium during bone regeneration.

ACS Style

Juan M. Díaz-Tocados; Carmen Herencia; Julio Martínez; Addy Montes De Oca; Maria E. Rodríguez-Ortiz; Noemi Vergara; Alfonso Blanco; Sonja Steppan; Yolanda Almadén; Mariano Rodriguez; Juan R. Muñoz-Castañeda. Magnesium Chloride promotes Osteogenesis through Notch signaling activation and expansion of Mesenchymal Stem Cells. Scientific Reports 2017, 7, 1 -12.

AMA Style

Juan M. Díaz-Tocados, Carmen Herencia, Julio Martínez, Addy Montes De Oca, Maria E. Rodríguez-Ortiz, Noemi Vergara, Alfonso Blanco, Sonja Steppan, Yolanda Almadén, Mariano Rodriguez, Juan R. Muñoz-Castañeda. Magnesium Chloride promotes Osteogenesis through Notch signaling activation and expansion of Mesenchymal Stem Cells. Scientific Reports. 2017; 7 (1):1-12.

Chicago/Turabian Style

Juan M. Díaz-Tocados; Carmen Herencia; Julio Martínez; Addy Montes De Oca; Maria E. Rodríguez-Ortiz; Noemi Vergara; Alfonso Blanco; Sonja Steppan; Yolanda Almadén; Mariano Rodriguez; Juan R. Muñoz-Castañeda. 2017. "Magnesium Chloride promotes Osteogenesis through Notch signaling activation and expansion of Mesenchymal Stem Cells." Scientific Reports 7, no. 1: 1-12.

Journal article
Published: 28 June 2017 in Clinical Science
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In chronic kidney disease patients, high phosphate (HP) levels are associated with cardiovascular disease, the major cause of morbidity and mortality. Since serum phosphate has been independently correlated with inflammation, the present study aimed to investigate an independent direct effect of HP as a pro-inflammatory factor in VSMCs. A possible modulatory effect of vitamin D (VitD) was also investigated. The study was performed in an in vitro model of human aortic smooth muscle cells (HASMCs). Incubation of cells in an HP (3.3 mM) medium caused an increased expression of the pro-inflammatory mediators intercellular adhesion molecule 1 (ICAM-1), interleukins (ILs) IL-1β, IL-6, IL-8 and tumour necrosis factor α (TNF-α) (not corroborated at the protein levels for ICAM-1), as well as an increase in reactive oxygen/nitrogen species (ROS/RNS) production. This was accompanied by the activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signalling as demonstrated by the increase in the nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells protein 65 (p65-NF-κΒ) assessed by Western blotting and confocal microscopy. Since all these events were attenuated by an antioxidant pre-incubation with the radical scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), it is suggested that the inflammatory response is upstream mediated by the ROS/RNS-induced activation of NF-κΒ. Addition of paricalcitol (PC) 3·10−8 M to cells in HP prevented the phosphate induced ROS/RNS increase, the activation of NF-κΒ and the cytokine up-regulation. A bimodal effect was observed, however, for different calcitriol (CTR) concentrations, 10−10 and 10−12 M attenuated but 10−8 M stimulated this phosphate induced pro-oxidative and pro-inflammatory response. Therefore, these findings provide novel mechanisms whereby HP may directly favour vascular dysfunctions and new insights into the protective effects exerted by VitD derivatives.

ACS Style

Julio Martínez; Carmen Herencia; Addy Montes De Oca; Juan M. Díaz-Tocados; Noemi Vergara; M. José Gómez-Luna; Silvia D. López-Argüello; Antonio Camargo; Esther Peralbo-Santaella; Maria E. Rodríguez-Ortiz; Antonio Canalejo; Mariano Rodriguez; Juan R. Muñoz-Castañeda; Yolanda Almadén. High phosphate induces a pro-inflammatory response by vascular smooth muscle cells and modulation by vitamin D derivatives. Clinical Science 2017, 131, 1449 -1463.

AMA Style

Julio Martínez, Carmen Herencia, Addy Montes De Oca, Juan M. Díaz-Tocados, Noemi Vergara, M. José Gómez-Luna, Silvia D. López-Argüello, Antonio Camargo, Esther Peralbo-Santaella, Maria E. Rodríguez-Ortiz, Antonio Canalejo, Mariano Rodriguez, Juan R. Muñoz-Castañeda, Yolanda Almadén. High phosphate induces a pro-inflammatory response by vascular smooth muscle cells and modulation by vitamin D derivatives. Clinical Science. 2017; 131 (13):1449-1463.

Chicago/Turabian Style

Julio Martínez; Carmen Herencia; Addy Montes De Oca; Juan M. Díaz-Tocados; Noemi Vergara; M. José Gómez-Luna; Silvia D. López-Argüello; Antonio Camargo; Esther Peralbo-Santaella; Maria E. Rodríguez-Ortiz; Antonio Canalejo; Mariano Rodriguez; Juan R. Muñoz-Castañeda; Yolanda Almadén. 2017. "High phosphate induces a pro-inflammatory response by vascular smooth muscle cells and modulation by vitamin D derivatives." Clinical Science 131, no. 13: 1449-1463.

Journal article
Published: 01 May 2017 in Nephrology Dialysis Transplantation
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INTRODUCTION AND AIMS: High serum levels of both FGF23 and phosphate (P) are associated with increased mortality in dialysis (HD) patients; thus, control of these parameters should benefit the patients. Phosphate stimulates FGF23 production; in chronic kidney disease (CKD) patients, reductions in serum P concentration produce decreases in serum concentration of FGF23. However, this effect remains to be demonstrated in HD patients. The aim of the present study was to evaluate in HD patients whether a sustained reduction or elevation in serum P concentration is associated with changes in FGF23.

ACS Style

Cristian Rodelo-Haad; M Victoria Pendon-Ruiz De Mier; Maria L Agûera-Morales; Sagrario Soriano; Maria A Alvarez-Lara; Pedro Aljama; Maria E Rodrìguez-Ortìz; Alejandro Martin-Malo; Juan R Muñoz-Castañeda; Mariano Rodriguez. MP690SERUM PHOSPHATE MODIFICATIONS ARE ASSOCIATED WITH CHANGES IN SERUM FGF23 AND C-REACTIVE PROTEIN. Nephrology Dialysis Transplantation 2017, 32, iii684 -iii684.

AMA Style

Cristian Rodelo-Haad, M Victoria Pendon-Ruiz De Mier, Maria L Agûera-Morales, Sagrario Soriano, Maria A Alvarez-Lara, Pedro Aljama, Maria E Rodrìguez-Ortìz, Alejandro Martin-Malo, Juan R Muñoz-Castañeda, Mariano Rodriguez. MP690SERUM PHOSPHATE MODIFICATIONS ARE ASSOCIATED WITH CHANGES IN SERUM FGF23 AND C-REACTIVE PROTEIN. Nephrology Dialysis Transplantation. 2017; 32 (suppl_3):iii684-iii684.

Chicago/Turabian Style

Cristian Rodelo-Haad; M Victoria Pendon-Ruiz De Mier; Maria L Agûera-Morales; Sagrario Soriano; Maria A Alvarez-Lara; Pedro Aljama; Maria E Rodrìguez-Ortìz; Alejandro Martin-Malo; Juan R Muñoz-Castañeda; Mariano Rodriguez. 2017. "MP690SERUM PHOSPHATE MODIFICATIONS ARE ASSOCIATED WITH CHANGES IN SERUM FGF23 AND C-REACTIVE PROTEIN." Nephrology Dialysis Transplantation 32, no. suppl_3: iii684-iii684.

Journal article
Published: 14 November 2016 in Scientific Reports
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Rats with normal renal function (Experiment 1, n = 12) and uninephrectomized (1/2Nx) rats (Experiment 2, n = 12) were fed diets with normal P (NP) and either normal (NF) or high fat (HF). Rats with intact renal function (Experiment 3, n = 12) were also fed NF or HF diets with high P (HP). Additionally, uremic (5/6Nx) rats (n = 16) were fed HP diets with NF or HF. Feeding the HF diets resulted in significant elevation of plasma FGF23 vs rats fed NF diets: Experiment 1, 593 ± 126 vs 157 ± 28 pg/ml (p < 0.01); Experiment 2, 538 ± 105 vs 250 ± 18 pg/ml (p < 0.05); Experiment 3, 971 ± 118 vs 534 ± 40 pg/ml (p < 0.01). Rats fed HF diets showed P retention and decreased renal klotho (ratio klotho/actin) vs rats fed NF diets: Experiment 1, 0.75 ± 0.06 vs 0.97 ± 0.02 (p < 0.01); Experiment 2, 0.69 ± 0.07 vs 1.12 ± 0.08 (p < 0.01); Experiment 3, 0.57 ± 0.19 vs 1.16 ± 0.15 (p < 0.05). Uremic rats fed HF diet showed more severe vascular calcification (VC) than rats fed NF diet (aortic Ca = 6.3 ± 1.4 vs 1.4 ± 0.1 mg/g tissue, p < 0.001). In conclusion, energy-rich diets increased plasma levels of FGF23, a known risk factor of cardiovascular morbidity and mortality. Even though FGF23 has major phosphaturic actions, feeding HF diets resulted in P retention, likely secondary to decreased renal klotho, and aggravated uremic VC.

ACS Style

Ana I. Raya; Rafael Rios; Carmen Pineda; Maria E. Rodriguez-Ortiz; Elisa Diez; Yolanda Almaden; Juan R. Muñoz-Castañeda; Mariano Rodriguez; Escolastico Aguilera-Tejero; Ignacio Lopez. Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats. Scientific Reports 2016, 6, 36881 .

AMA Style

Ana I. Raya, Rafael Rios, Carmen Pineda, Maria E. Rodriguez-Ortiz, Elisa Diez, Yolanda Almaden, Juan R. Muñoz-Castañeda, Mariano Rodriguez, Escolastico Aguilera-Tejero, Ignacio Lopez. Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats. Scientific Reports. 2016; 6 (1):36881.

Chicago/Turabian Style

Ana I. Raya; Rafael Rios; Carmen Pineda; Maria E. Rodriguez-Ortiz; Elisa Diez; Yolanda Almaden; Juan R. Muñoz-Castañeda; Mariano Rodriguez; Escolastico Aguilera-Tejero; Ignacio Lopez. 2016. "Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats." Scientific Reports 6, no. 1: 36881.

Research article
Published: 03 June 2016 in PLOS ONE
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Periodontitis is a complex pathology characterized by the loss of alveolar bone. The causes and the mechanisms that promote this bone resorption still remain unknown. The knowledge of the critical regulators involved in the alteration of alveolar bone homeostasis is of great importance for developing molecular therapies. Procaine is an anesthetic drug with demethylant properties, mainly used by dentists in oral surgeries. The inhibitor role of Wnt signaling of procaine was described in vitro in colon cancer cells. In this work we evaluated the role of procaine (1 uM) in osteo/odontogenesis of rat bone marrow mesenchymal stem cells. Similarly, the mechanisms whereby procaine achieves these effects were also studied. Procaine administration led to a drastic decrease of calcium content, alkaline phosphatase activity, alizarin red staining and an increase in the expression of Matrix Gla Protein. With respect to osteo/odontogenic markers, procaine decreased early and mature osteo/odontogenic markers. In parallel, procaine inhibited canonical Wnt/β-catenin pathway, observing a loss of nuclear β-catenin, a decrease in Lrp5 and Frizzled 3, a significant increase of sclerostin and Gsk3β and an increase of phosphorylated β-catenin. The combination of osteo/odontogenic stimuli and Lithium Chloride decreased mRNA expression of Gsk3β, recovered by Procaine. Furthermore it was proved that Procaine alone dose dependently increases the expression of Gsk3β and β-catenin phosphorylation. These effects of procaine were also observed on mature osteoblast. Interestingly, at this concentration of procaine no demethylant effects were observed. Our results demonstrated that procaine administration drastically reduced the mineralization and osteo/odontogenesis of bone marrow mesenchymal stem cells inhibiting Wnt/β-catenin pathway through the increase of Gsk3β expression and β-catenin phosphorylation.

ACS Style

Carmen Herencia; Juan Miguel Diaz-Tocados; Lidia Jurado; Addy Montes De Oca; Maria Encarnación Rodríguez-Ortiz; Carmen Martín-Alonso; Julio Martínez; Noemi Vergara; Mariano Rodriguez; Yolanda Almadén; Juan R. Muñoz-Castañeda. Procaine Inhibits Osteo/Odontogenesis through Wnt/β-Catenin Inactivation. PLOS ONE 2016, 11, e0156788 .

AMA Style

Carmen Herencia, Juan Miguel Diaz-Tocados, Lidia Jurado, Addy Montes De Oca, Maria Encarnación Rodríguez-Ortiz, Carmen Martín-Alonso, Julio Martínez, Noemi Vergara, Mariano Rodriguez, Yolanda Almadén, Juan R. Muñoz-Castañeda. Procaine Inhibits Osteo/Odontogenesis through Wnt/β-Catenin Inactivation. PLOS ONE. 2016; 11 (6):e0156788.

Chicago/Turabian Style

Carmen Herencia; Juan Miguel Diaz-Tocados; Lidia Jurado; Addy Montes De Oca; Maria Encarnación Rodríguez-Ortiz; Carmen Martín-Alonso; Julio Martínez; Noemi Vergara; Mariano Rodriguez; Yolanda Almadén; Juan R. Muñoz-Castañeda. 2016. "Procaine Inhibits Osteo/Odontogenesis through Wnt/β-Catenin Inactivation." PLOS ONE 11, no. 6: e0156788.

Research communication
Published: 09 December 2015 in The FASEB Journal
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Clinical and epidemiologic studies reveal an association between vitamin D deficiency and increased risk of cardiovascular disease. Because vascular smooth muscle cell (VSMC)-derived tissue factor (TF) is suggested to be critical for arterial thrombosis, we investigated whether the vitamin D molecules calcitriol and paricalcitol could reduce the expression of TF induced by the proinflammatory cytokine TNF-α in human aortic VSMCs. We found that, compared with controls, incubation with TNF-α increased TF expression and procoagulant activity in a NF-κB-dependent manner, as deduced from the increased nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells protein 65 (p65-NF-κB) and direct interaction of NF-kB to the TF promoter. This was accompanied by the up-regulation of TF signaling mediator protease-activated receptor 2 (PAR-2) expression and by the down-regulation of vitamin D receptor expression in a miR-346-dependent way. However, addition of calcitriol or paricalcitol blunted the TNF-α-induced TF expression and activity (2.01 ± 0.24 and 1.32 ± 0.14 vs. 3.02 ± 0.39 pmol/mg protein, P < 0.05), which was associated with down-regulation of NF-kB signaling and PAR-2 expression, as well as with restored levels of vitamin D receptor and enhanced expression of TF pathway inhibitor. Our data suggest that inflammation promotes a prothrombotic state through the up-regulation of TF function in VSMCs and that the beneficial cardiovascular effects of vitamin D may be partially due to decreases in TF expression and its activity in VSMCs.—Martinez-Moreno, J. M., Herencia, C., Montes de Oca, A., Muñoz-Castañeda, J. R., Rodríguez-Ortiz, M. E., Díaz-Tocados, J. M., Peralbo-Santaella, E., Camargo, A., Canalejo, A., Rodriguez, M., Velasco-Gimena, F., Almaden, Y., Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells. FASEB J. 30, 1367–1376 (2016). www.fasebj.org

ACS Style

Julio M. Martinez‐Moreno; Carmen Herencia; Addy Montes de Oca; Juan R. Muñoz‐Castañeda; M. Encarnación Rodríguez‐Ortiz; Juan M. Díaz‐Tocados; Esther Peralbo‐Santaella; Antonio Camargo; Antonio Canalejo; Mariano Rodriguez; Francisco Velasco‐Gimena; Yolanda Almaden. Vitamin D modulates tissue factor and protease‐activated receptor 2 expression in vascular smooth muscle cells. The FASEB Journal 2015, 30, 1367 -1376.

AMA Style

Julio M. Martinez‐Moreno, Carmen Herencia, Addy Montes de Oca, Juan R. Muñoz‐Castañeda, M. Encarnación Rodríguez‐Ortiz, Juan M. Díaz‐Tocados, Esther Peralbo‐Santaella, Antonio Camargo, Antonio Canalejo, Mariano Rodriguez, Francisco Velasco‐Gimena, Yolanda Almaden. Vitamin D modulates tissue factor and protease‐activated receptor 2 expression in vascular smooth muscle cells. The FASEB Journal. 2015; 30 (3):1367-1376.

Chicago/Turabian Style

Julio M. Martinez‐Moreno; Carmen Herencia; Addy Montes de Oca; Juan R. Muñoz‐Castañeda; M. Encarnación Rodríguez‐Ortiz; Juan M. Díaz‐Tocados; Esther Peralbo‐Santaella; Antonio Camargo; Antonio Canalejo; Mariano Rodriguez; Francisco Velasco‐Gimena; Yolanda Almaden. 2015. "Vitamin D modulates tissue factor and protease‐activated receptor 2 expression in vascular smooth muscle cells." The FASEB Journal 30, no. 3: 1367-1376.

Original article
Published: 13 August 2015 in European Journal of Clinical Investigation
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Background Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). Low magnesium levels are associated with VC, and recent in vitro studies confirm a protective role of magnesium, which is mediated by its entry into the VSMCs through the Transient Receptor Potential Melastatin 7 (TRPM7) channel. The role of Angiotensin II (Ang II) on VC is still unclear. As Ang II is able to stimulate TRPM7 activity, we hypothesize that it might prevent VC. Thus, the aim of this study was to dissect the direct effect of Ang II on VC. Materials and methods We worked with a model of high phosphate (HP)‐induced calcification in human aortic smooth muscle cells, which resembles the CKD‐related VC. Results Addition of Ang II to cells growing in HP decreased calcification, which was associated with the upregulation of the osteogenic factors BMP2, Runx2/Cbfa1, Osterix and ALP. A reduction of magnesium entry into the HP‐calcifying cells was found. The treatment with Ang II avoided this reduction, which was reversed by the cotreatment with the TRPM7‐inhibitor 2‐APB. The protective effect of Ang II was related to AT1R‐induced ERK1/2 MAPKinase activation. HP‐induced calcification was also associated with the upregulation of the canonical Wnt/beta‐catenin pathway, while its downregulation was related to attenuation of calcification by Ang II. Conclusion As hypothesized, Ang II prevented phosphate‐induced calcification in VSMCs, which appears mediated by the increase of magnesium influx and by the activation of the ERK1/2 and the inhibition of the canonical Wnt/beta‐catenin signalling pathways.

ACS Style

Carmen Herencia; Mª Encarnación Rodríguez-Ortiz; Juan R. Muñoz-Castañeda; Julio Martínez; Rocío Canalejo; Addy Montes De Oca; Juan M. Díaz-Tocados; Esther Peralbo-Santaella; Carmen Marín; Antonio Canalejo; Mariano Rodriguez; Yolanda Almadén. Angiotensin II prevents calcification in vascular smooth muscle cells by enhancing magnesium influx. European Journal of Clinical Investigation 2015, 45, 1129 -1144.

AMA Style

Carmen Herencia, Mª Encarnación Rodríguez-Ortiz, Juan R. Muñoz-Castañeda, Julio Martínez, Rocío Canalejo, Addy Montes De Oca, Juan M. Díaz-Tocados, Esther Peralbo-Santaella, Carmen Marín, Antonio Canalejo, Mariano Rodriguez, Yolanda Almadén. Angiotensin II prevents calcification in vascular smooth muscle cells by enhancing magnesium influx. European Journal of Clinical Investigation. 2015; 45 (11):1129-1144.

Chicago/Turabian Style

Carmen Herencia; Mª Encarnación Rodríguez-Ortiz; Juan R. Muñoz-Castañeda; Julio Martínez; Rocío Canalejo; Addy Montes De Oca; Juan M. Díaz-Tocados; Esther Peralbo-Santaella; Carmen Marín; Antonio Canalejo; Mariano Rodriguez; Yolanda Almadén. 2015. "Angiotensin II prevents calcification in vascular smooth muscle cells by enhancing magnesium influx." European Journal of Clinical Investigation 45, no. 11: 1129-1144.

Journal article
Published: 01 July 2015 in Biochemical Pharmacology
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During the course of cholestatic liver diseases, the toxic effect of bile acids accumulation has been related to the decreased expression of endothelial nitric oxide synthase (NOS-3) and cellular oxidative stress increase. In the present study, we have investigated the relationship between these two biological events. In the human hepatocarcinoma cell line HepG2, cytotoxic response to GCDCA was characterized by the reduced activity of the respiratory complexes II+III, the increased expression and activation of the transcription factor Sp1, and a higher binding capacity of this at positions -1386, -632 and -104 of the NOS-3 promoter (pNOS-3). This was associated with a decreased promoter activity and a consequent reduction of NOS-3 expression. The use of antioxidants in GCDCA-treated cells caused a lower activation of Sp1 and the recovery of the pNOS-3 activity and NOS-3 expression and activity. Similarly, the specific inhibition of Sp1 resulted in the improvement of NOS-3 expression. Both, antioxidant treatment and Sp1 inhibition were associated with the reduction of cell death-related parameters. Bile duct ligation in rats confirmed in vitro results concerning the activation of Sp1 and the reduction of NOS-3 expression. Our results provide direct evidence for the involvement of Sp1 in the regulation of NOS-3 expression during cholestasis. Thus, the identification of Sp1 as a potential negative regulator of NOS-3 expression represents a new mechanism by which the accumulation of bile acids causes a cytotoxic effect through the oxidative stress increase, and provides a new potential target in cholestatic liver diseases.

ACS Style

Sandra González-Rubio; Laura López-Sánchez; Juan Muñoz-Castañeda; Clara I. Linares; Patricia Aguilar-Melero; Manuel Rodríguez-Perálvarez; Rafael Sánchez-Sánchez; Ana Fernández-Álvarez; Marta Casado; Jose L. Montero-Álvarez; Antonio Rodríguez-Ariza; Jordi Muntané; Manuel de la Mata; Gustavo Ferrín. GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner. Biochemical Pharmacology 2015, 96, 39 -51.

AMA Style

Sandra González-Rubio, Laura López-Sánchez, Juan Muñoz-Castañeda, Clara I. Linares, Patricia Aguilar-Melero, Manuel Rodríguez-Perálvarez, Rafael Sánchez-Sánchez, Ana Fernández-Álvarez, Marta Casado, Jose L. Montero-Álvarez, Antonio Rodríguez-Ariza, Jordi Muntané, Manuel de la Mata, Gustavo Ferrín. GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner. Biochemical Pharmacology. 2015; 96 (1):39-51.

Chicago/Turabian Style

Sandra González-Rubio; Laura López-Sánchez; Juan Muñoz-Castañeda; Clara I. Linares; Patricia Aguilar-Melero; Manuel Rodríguez-Perálvarez; Rafael Sánchez-Sánchez; Ana Fernández-Álvarez; Marta Casado; Jose L. Montero-Álvarez; Antonio Rodríguez-Ariza; Jordi Muntané; Manuel de la Mata; Gustavo Ferrín. 2015. "GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner." Biochemical Pharmacology 96, no. 1: 39-51.