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Article ; Online: Effect of the structural modification of Candesartan with Zinc on hypertension and left ventricular hypertrophy.

Martinez, Valeria R / Martins Lima, Augusto / Stergiopulos, Nikolaous / Velez Rueda, Jorge O / Islas, Maria S / Griera, Mercedes / Calleros, Laura / Rodriguez Puyol, Manuel / Jaquenod de Giusti, Carolina / Portiansky, Enrique L / Ferrer, Evelina G / De Giusti, Verónica / Williams, Patricia A M

European journal of pharmacology

2023 Volume 946, Page(s) 175654

Abstract: Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously ... ...

Abstract	Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT
MeSH term(s)	Animals ; Rats ; Antihypertensive Agents/chemistry ; Antihypertensive Agents/pharmacology ; Biphenyl Compounds/pharmacology ; Blood Pressure ; Hypertension/complications ; Hypertension/drug therapy ; Hypertrophy, Left Ventricular/drug therapy ; Matrix Metalloproteinase 2 ; Myocytes, Cardiac ; Rats, Inbred SHR ; Tetrazoles/pharmacology ; Tetrazoles/therapeutic use ; Zinc/pharmacology
Chemical Substances	Antihypertensive Agents ; Biphenyl Compounds ; candesartan (S8Q36MD2XX) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Tetrazoles ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2023-03-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2023.175654
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Zs.A 522: Show issues

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Article ; Online: Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation.

Campillo, Sofía / Bohorquez, Lourdes / Gutiérrez-Calabrés, Elena / García-Ayuso, Diego / Miguel, Verónica / Griera, Mercedes / Calle, Yolanda / de Frutos, Sergio / Rodríguez-Puyol, Manuel / Rodríguez-Puyol, Diego / Calleros, Laura

Experimental & molecular medicine

2022 Volume 54, Issue 3, Page(s) 226–238

Abstract: Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial ... ...

Abstract	Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD.
MeSH term(s)	Animals ; Cell Adhesion ; Cresols ; Cytoskeletal Proteins/metabolism ; Humans ; Indican/metabolism ; Indican/pharmacology ; Mice ; Monocytes ; Podosomes/metabolism ; Protein Serine-Threonine Kinases/metabolism ; THP-1 Cells
Chemical Substances	Cresols ; Cytoskeletal Proteins ; 4-cresol (1MXY2UM8NV) ; integrin-linked kinase (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Indican (N187WK1Y1J)
Language	English
Publishing date	2022-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1328915-9
ISSN	2092-6413 ; 1226-3613 ; 0378-8512
ISSN (online)	2092-6413
ISSN	1226-3613 ; 0378-8512
DOI	10.1038/s12276-022-00738-8
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Zs.A 4775: Show issues

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Article ; Online: Serum and Urinary Soluble α-Klotho as Markers of Kidney and Vascular Impairment.

Martín-Vírgala, Julia / Fernández-Villabrille, Sara / Martín-Carro, Beatriz / Tamargo-Gómez, Isaac / Navarro-González, Juan F / Mora-Fernández, Carmen / Calleros, Laura / Astudillo-Cortés, Elena / Avello-Llano, Noelia / Mariño, Guillermo / Dusso, Adriana S / Alonso-Montes, Cristina / Panizo, Sara / Cannata-Andía, Jorge B / Naves-Díaz, Manuel / Carrillo-López, Natalia

Nutrients

2023 Volume 15, Issue 6

Abstract: This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the ... ...

Abstract	This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the effects of sKlotho on vascular smooth muscle cells (VSMCs) osteogenic differentiation and to evaluate the role of autophagy in this process. Experimental studies were conducted in CKD mice fed a normal phosphorus (CKD+NP) or high phosphorus (CKD+HP) diet for 14 weeks. The patients' study was performed in CKD stages 2-5 and in vitro studies which used VSMCs exposed to non-calcifying medium or calcifying medium with or without sKlotho. The CKD experimental model showed that the CKD+HP group reached the highest serum PTH, P and FGF23 levels, but the lowest serum and urinary sKlotho levels. In addition, a positive correlation between serum sKlotho and kidney α-Klotho was found. CKD mice showed aortic osteogenic differentiation, together with increased autophagy. The human CKD study showed that the decline in serum sKlotho is previous to the rise in FGF23. In addition, both serum sKlotho and FGF23 levels correlated with kidney function. Finally, in VSMCs, the addition of sKlotho prevented osteogenic differentiation and induced autophagy. It can be concluded that serum sKlotho was the earliest CKD-MBD biomarker, a reliable indicator of kidney α-Klotho and that might protect against osteogenic differentiation by increasing autophagy. Nevertheless, further studies are needed to investigate the mechanisms of this possible protective effect.
MeSH term(s)	Humans ; Mice ; Animals ; Klotho Proteins ; Glucuronidase ; Chronic Kidney Disease-Mineral and Bone Disorder ; Osteogenesis ; Fibroblast Growth Factors ; Kidney ; Renal Insufficiency, Chronic ; Phosphorus ; Minerals ; Biomarkers
Chemical Substances	Klotho Proteins (EC 3.2.1.31) ; Glucuronidase (EC 3.2.1.31) ; Fibroblast Growth Factors (62031-54-3) ; Phosphorus (27YLU75U4W) ; Minerals ; Biomarkers
Language	English
Publishing date	2023-03-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15061470
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Article ; Online: Interplay between extracellular matrix components and cellular and molecular mechanisms in kidney fibrosis.

Rayego-Mateos, Sandra / Campillo, Sofia / Rodrigues-Diez, Raúl R / Tejera-Muñoz, Antonio / Marquez-Exposito, Laura / Goldschmeding, Roel / Rodríguez-Puyol, Diego / Calleros, Laura / Ruiz-Ortega, Marta

Clinical science (London, England : 1979)

2021 Volume 135, Issue 16, Page(s) 1999–2029

Abstract: Chronic kidney disease (CKD) is characterized by pathological accumulation of extracellular matrix (ECM) proteins in renal structures. Tubulointerstitial fibrosis is observed in glomerular diseases as well as in the regeneration failure of acute kidney ... ...

Abstract	Chronic kidney disease (CKD) is characterized by pathological accumulation of extracellular matrix (ECM) proteins in renal structures. Tubulointerstitial fibrosis is observed in glomerular diseases as well as in the regeneration failure of acute kidney injury (AKI). Therefore, finding antifibrotic therapies comprises an intensive research field in Nephrology. Nowadays, ECM is not only considered as a cellular scaffold, but also exerts important cellular functions. In this review, we describe the cellular and molecular mechanisms involved in kidney fibrosis, paying particular attention to ECM components, profibrotic factors and cell-matrix interactions. In response to kidney damage, activation of glomerular and/or tubular cells may induce aberrant phenotypes characterized by overproduction of proinflammatory and profibrotic factors, and thus contribute to CKD progression. Among ECM components, matricellular proteins can regulate cell-ECM interactions, as well as cellular phenotype changes. Regarding kidney fibrosis, one of the most studied matricellular proteins is cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), currently considered as a fibrotic marker and a potential therapeutic target. Integrins connect the ECM proteins to the actin cytoskeleton and several downstream signaling pathways that enable cells to respond to external stimuli in a coordinated manner and maintain optimal tissue stiffness. In kidney fibrosis, there is an increase in ECM deposition, lower ECM degradation and ECM proteins cross-linking, leading to an alteration in the tissue mechanical properties and their responses to injurious stimuli. A better understanding of these complex cellular and molecular events could help us to improve the antifibrotic therapies for CKD.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Cell Physiological Phenomena ; Extracellular Matrix/metabolism ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fibrosis ; Humans ; Kidney/metabolism ; Kidney/pathology ; Mice ; Renal Insufficiency, Chronic/diagnosis ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/pathology
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-08-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20201016
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Article ; Online: Integrin Linked Kinase (ILK) Downregulation as an Early Event During the Development of Metabolic Alterations in a Short-Term High Fat Diet Mice Model.

Hatem-Vaquero, Marco / Griera, Mercedes / Garcia-Ayuso, Diego / Campillo, Sofia / Bohorquez, Lourdes / Calleros, Laura / Rodriguez-Puyol, Diego / Rodriguez-Puyol, Manuel / de Frutos, Sergio

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2020 Volume 54, Issue 1, Page(s) 71–87

Abstract: Background/aims: Diabetes type 2, metabolic syndrome or non-alcoholic fatty liver disease are insulin resistance-related metabolic disorders, which lack a better prognosis before their full establishment. We studied the importance of the intracellular ... ...

Abstract	Background/aims: Diabetes type 2, metabolic syndrome or non-alcoholic fatty liver disease are insulin resistance-related metabolic disorders, which lack a better prognosis before their full establishment. We studied the importance of the intracellular scaffold protein integrin linked kinaes (ILK) as a key modulator in the initial pathogenesis and the early progression of those insulin resistance- related disorders. Methods: Adult mice with a global transgenic downregulation of ILK expression (cKD-ILK) and littermates without that depletion (CT) were fed with either standard (STD) or high fat (HFD) diets during 2 and 6 weeks. Weights, blood glucose and other systemic biochemical parameters were determined in animals under fasting conditions and after glucose or pyruvate intraperitoneal injections to test their tolerance. In RNA or proteins extracted from insulin-sensitive tissues, we determined by reverse transcription-quantitative PCR and western blot the expression of ILK, metabolites transporters and other metabolism and inflammatory markers. Glucose uptake capacity was studied in freshly isolated tissues. Results: HFD feeding was able to early and progressively increase glycaemia, insulinemia, circulating glycerol, body weight gain, liver-mediated gluconeogenesis along this time lapse, but cKD-ILK have all these systemic misbalances exacerbated compared to CT in the same HFD time lapse. Interestingly, the tisular expression of ILK in HFD-fed CT was dramatically downregulated in white adipose tissue (WAT), skeletal muscle and liver at the same extent of the original ILK downregulation of cKD-ILK. We previously published that basal STD-fed cKD-ILK compared to basal STD-CT have different expression of glucose transporters GLUT4 in WAT and skeletal muscle. In the same STD-fed cKD-ILK, we observed here the increased expressions of hepatic GLUT2 and WAT pro-inflammatory cytokines TNF-α and MCP-1. The administration of HFD exacerbated the expression changes in cKD-ILK of these and other markers related to the imbalanced metabolism observed, such as WAT lipolysis (HSL), hepatic gluconeogenesis (PCK-1) and glycerol transport (AQP9). Conclusion: ILK expression may be taken as a predictive determinant of metabolic disorders establishment, because its downregulation seems to correlate with the early imbalance of glucose and glycerol transport and the subsequent loss of systemic homeostasis of these metabolites.
MeSH term(s)	Animals ; Diet, High-Fat/adverse effects ; Down-Regulation ; Female ; Gluconeogenesis ; Inflammation/etiology ; Inflammation/genetics ; Insulin Resistance ; Lipolysis ; Male ; Metabolic Diseases/etiology ; Metabolic Diseases/genetics ; Mice ; Mice, Inbred BALB C ; Protein-Serine-Threonine Kinases/genetics
Chemical Substances	integrin-linked kinase (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2020-01-23
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000206
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Zs.A 3160: Show issues

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Article ; Online: Dual inhibition of (V600E)BRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism.

Sánchez-Hernández, Irene / Baquero, Pablo / Calleros, Laura / Chiloeches, Antonio

Cancer letters

2012 Volume 314, Issue 2, Page(s) 244–255

Abstract: BRAF is a main oncogene in human melanomas. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with RAF inhibitor Sorafenib induces apoptosis in NPA melanoma cells expressing oncogenic (V600E)BRAF. This effect is ... ...

Abstract	BRAF is a main oncogene in human melanomas. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with RAF inhibitor Sorafenib induces apoptosis in NPA melanoma cells expressing oncogenic (V600E)BRAF. This effect is mediated through a MEK/ERK-independent mechanism, since treatment with the MEK inhibitor U0126 does not exert any effect. Moreover, we demonstrate that inhibition of the PI3K/AKT/mTOR cascade alone does not increase apoptosis in these cells. However, the blockage of this pathway in cells lacking either BRAF expression or activity cooperates to induce higher levels of apoptosis than those achieved by inhibition of BRAF alone. Consistently, we demonstrate that abrogation of BRAF expression increases AKT and mTOR phosphorylation, suggesting the existence of a compensatory pro-survival mechanism after BRAF depletion. Together, our data provide a rationale for dual targeting of BRAF and PI3K/AKT/mTOR signalling to effectively control melanoma disease.
MeSH term(s)	Apoptosis/drug effects ; Cell Line, Tumor ; Extracellular Signal-Regulated MAP Kinases/physiology ; Humans ; Melanoma/drug therapy ; Melanoma/pathology ; Mitogen-Activated Protein Kinase Kinases/physiology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/physiology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/physiology ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/physiology ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/physiology
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2012-01-28
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2011.09.037
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Zs.A 1177: Show issues

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Article ; Online: Chronic kidney disease induced by an adenine rich diet upregulates integrin linked kinase (ILK) and its depletion prevents the disease progression.

de Frutos, Sergio / Luengo, Alicia / García-Jérez, Andrea / Hatem-Vaquero, Marco / Griera, Mercedes / O'Valle, Francisco / Rodríguez-Puyol, Manuel / Rodríguez-Puyol, Diego / Calleros, Laura

Biochimica et biophysica acta. Molecular basis of disease

2019 Volume 1865, Issue 6, Page(s) 1284–1297

Abstract: Kidney fibrosis is one of the main pathological findings of progressive chronic kidney disease (CKD) although the pathogenesis of renal scar formation remains incompletely explained. Integrin-linked kinase (ILK), a major scaffold protein between the ... ...

Abstract	Kidney fibrosis is one of the main pathological findings of progressive chronic kidney disease (CKD) although the pathogenesis of renal scar formation remains incompletely explained. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix (ECM) and intracellular signaling pathways, is involved in several pathophysiological processes during renal damage. However, ILK contribution in the CKD progress remains to be fully elucidated. In the present work, we studied 1) the renal functional and structural consequences of CKD genesis and progression when ILK is depleted and 2) the potential of ILK depletion as a therapeutic approach to delay CKD progression. We induced an experimental CKD model, based on an adenine-supplemented diet on adult wild-type (WT) and ILK-depleted mice, with a tubulointerstitial damage profile resembling that is observed in human CKD. The adenine diet induced in WT mice a progressive increase in plasma creatinine and urea concentrations. In the renal cortex it was also observed tubular damage, interstitial fibrosis and progressive increased ECM components, pro-inflammatory and chemo-attractant cytokines, EMT markers and TGF-β1 expressions. These observations were highly correlated to a simultaneous increase of ILK expression and activity. In adenine-fed transgenic ILK-depleted mice, all these changes were prevented. Additionally, we evaluated the potential role of ILK depletion to be applied after the disease induction, as an effective approach to interventions in human CKD subjects. In this scenario, two weeks after the establishment of adenine-induced CKD, ILK was abrogated in WT mice and stabilized renal damage, avoiding CKD progression. We propose ILK to be a potential target to delay renal disease progression.
MeSH term(s)	Actins/genetics ; Actins/metabolism ; Adenine/administration & dosage ; Animals ; Cadherins/genetics ; Cadherins/metabolism ; Creatinine/blood ; Diet ; Disease Models, Animal ; Extracellular Matrix/metabolism ; Extracellular Matrix/pathology ; Fibrosis ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Kidney Tubules/metabolism ; Kidney Tubules/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Protein-Serine-Threonine Kinases/deficiency ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Renal Insufficiency, Chronic/chemically induced ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/pathology ; Signal Transduction ; Snail Family Transcription Factors/genetics ; Snail Family Transcription Factors/metabolism ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism ; Urea/blood
Chemical Substances	Actins ; Cadherins ; Cdh1 protein, mouse ; Snai1 protein, mouse ; Snail Family Transcription Factors ; Tgfb1 protein, mouse ; Transforming Growth Factor beta1 ; alpha-smooth muscle actin, mouse ; Urea (8W8T17847W) ; Creatinine (AYI8EX34EU) ; integrin-linked kinase (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Adenine (JAC85A2161)
Language	English
Publishing date	2019-02-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2019.01.024
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Article: Dual inhibition of ⱽ⁶⁰⁰ᴱBRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism

Sánchez-Hernández, Irene / Baquero, Pablo / Calleros, Laura / Chiloeches, Antonio

Cancer letters. 2012 Jan. 28, v. 314, no. 2

2012

Abstract	BRAF is a main oncogene in human melanomas. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with RAF inhibitor Sorafenib induces apoptosis in NPA melanoma cells expressing oncogenic ⱽ⁶⁰⁰ᴱBRAF. This effect is mediated through a MEK/ERK-independent mechanism, since treatment with the MEK inhibitor U0126 does not exert any effect. Moreover, we demonstrate that inhibition of the PI3K/AKT/mTOR cascade alone does not increase apoptosis in these cells. However, the blockage of this pathway in cells lacking either BRAF expression or activity cooperates to induce higher levels of apoptosis than those achieved by inhibition of BRAF alone. Consistently, we demonstrate that abrogation of BRAF expression increases AKT and mTOR phosphorylation, suggesting the existence of a compensatory pro-survival mechanism after BRAF depletion. Together, our data provide a rationale for dual targeting of BRAF and PI3K/AKT/mTOR signalling to effectively control melanoma disease.
Keywords	apoptosis ; humans ; melanoma ; oncogenes ; phosphorylation
Language	English
Dates of publication	2012-0128
Size	p. 244-255.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2011.09.037
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 1177: Show issues

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Article ; Online: Contribution of uraemic toxins to the vascular fibrosis associated with chronic kidney disease.

Hatem-Vaquero, Marco / de Frutos, Sergio / Luengo, Alicia / González Abajo, Alba / Griera, Mercedes / Rodríguez-Puyol, Manuel / Rodríguez-Puyol, Diego / Calleros, Laura

Nefrologia

2018 Volume 38, Issue 6, Page(s) 639–646

Abstract: Background: Patients with chronic kidney disease present with an accumulation of uraemic toxins, which have been identified as pathogenic agents associated with cardiovascular mortality, which is very high is this patient group. A phenomenon common to ... ...

Title translation	Contribución de las toxinas urémicas a la fibrosis vascular asociada a la enfermedad renal crónica.
Abstract	Background: Patients with chronic kidney disease present with an accumulation of uraemic toxins, which have been identified as pathogenic agents associated with cardiovascular mortality, which is very high is this patient group. A phenomenon common to the progressive renal dysfunction and associated vascular damage, is the abnormal accumulation of extracellular matrix (ECM) proteins in the renal or vascular structures. Objective: To determine the contribution of uraemia or the uraemic toxins to the production of cytokinins and ECM in aortas of uraemic animals or human aortic smooth muscle cells (HASMCs). Materials and methods: Mice were used with uraemia induced by a diet rich in adenine (0.2%) for 2, 4 or 6 weeks. Kidney function was evaluated by means of urine volume, plasma levels of creatinine, urea, fractional excretion of sodium, and vascular damage using histology, as well as protein expression using RT-qPCR. The HASMCs were incubated in vitro with uraemic toxins: p-cresol 10-100 (μg/ml) and indoxyl-sulphate25-100 (μg/ml) alone or simultaneously. The protein expression was evaluated using Western blot and confocal microscopy. Results: The administration of adenine produced progressive kidney damage in the mice, thickening of the aortic wall, and increasing the expression of TGF-β1 and ECM proteins. The toxins at high doses and combined also induced the expression of TGF-β1 and ECM proteins by the HASMCs. Conclusions: The uraemia produced by an adenine rich diet or high doses of uraemic toxins induced the abnormal deposit of ECM proteins in the vascular wall or its production by HASMCs. The understanding of the mechanisms that underlie this pathophysiological process may be useful in the prevention of cardiovascular damage associated with the progress of chronic kidney disease, a disease, at the moment that is irreversible and occasional silent until its diagnosis in advanced stages.
MeSH term(s)	Adenine/administration & dosage ; Animals ; Blood Vessels/pathology ; Cytokines/physiology ; Extracellular Matrix Proteins/physiology ; Fibrosis/etiology ; Male ; Mice ; Mice, Inbred C57BL ; Renal Insufficiency, Chronic/complications ; Toxins, Biological/physiology ; Transforming Growth Factor beta1/physiology ; Uremia/complications
Chemical Substances	Cytokines ; Extracellular Matrix Proteins ; Toxins, Biological ; Transforming Growth Factor beta1 ; Adenine (JAC85A2161)
Language	Spanish
Publishing date	2018-10-15
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2837917-2
ISSN	2013-2514 ; 2013-2514
ISSN (online)	2013-2514
ISSN	2013-2514
DOI	10.1016/j.nefro.2018.07.008
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Article ; Online: H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

Martín-Sánchez, Paloma / Luengo, Alicia / Griera, Mercedes / Orea, María Jesús / López-Olañeta, Marina / Chiloeches, Antonio / Lara-Pezzi, Enrique / de Frutos, Sergio / Rodríguez-Puyol, Manuel / Calleros, Laura / Rodríguez-Puyol, Diego

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2018 Volume 32, Issue 2, Page(s) 920–934

Abstract: Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H- ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)-dependent mechanism. ...

Abstract	Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H- ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)-dependent mechanism. In this study, we analyzed the consequences of H- ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H -ras
MeSH term(s)	Angiotensin II/adverse effects ; Angiotensin II/pharmacology ; Animals ; Cardiomegaly/chemically induced ; Cardiomegaly/enzymology ; Cardiomegaly/genetics ; Cardiomegaly/prevention & control ; Cyclic GMP-Dependent Protein Kinase Type I/genetics ; Cyclic GMP-Dependent Protein Kinase Type I/metabolism ; Embryo, Mammalian/enzymology ; Embryo, Mammalian/pathology ; Enzyme Activation/drug effects ; Enzyme Activation/genetics ; Fibroblasts/enzymology ; Fibroblasts/pathology ; Gene Deletion ; Glycogen Synthase Kinase 3 beta/genetics ; Glycogen Synthase Kinase 3 beta/metabolism ; Hypertension/chemically induced ; Hypertension/enzymology ; Hypertension/pathology ; MAP Kinase Signaling System ; Mice ; Mice, Knockout ; Proto-Oncogene Proteins p21(ras)/deficiency
Chemical Substances	Angiotensin II (11128-99-7) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, mouse (EC 2.7.11.1) ; Cyclic GMP-Dependent Protein Kinase Type I (EC 2.7.11.12) ; Prkg1 protein, mouse (EC 2.7.11.12) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2018-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201700134RRRR
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