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1.
Rev. chil. obstet. ginecol. (En línea) ; 88(3): 183-190, jun. 2023. tab, graf
Artículo en Español | LILACS | ID: biblio-1515208

RESUMEN

La Sociedad Chilena de Obstetricia y Ginecología (SOCHOG) y la Sociedad Chilena de Ultrasonido en Medicina y Biología (SOCHUMB) convocaron a un comité de expertos en el tema de ultrasonido y crecimiento fetal con el fin de proponer utilizar la curva fetal que mejor se adapte a la población chilena. Luego de la discusión, al no contar con curvas chilenas de crecimiento fetal, se concluye proponer que la curva estándar de la Organización Mundial de la Salud (OMS) sería la indicada dada la calidad de su metodología y por ser multicéntrica.


The Chilean Society of Obstetrics and Gynecology (SOCHOG) and the Chilean Society of Ultrasound in Medicine and Biology (SOCHUMB) have convened a committee of experts on the subject of ultrasound and fetal growth in order to propose using the fetal curve that best adapts to the Chilean population. After the discussion, since there are no Chilean fetal growth curves, it is concluded that the World Health Organization (WHO) standard curve would be the one to use given the quality of its methodology and the fact that it is multicentric.


Asunto(s)
Humanos , Femenino , Embarazo , Organización Mundial de la Salud , Ultrasonografía Prenatal/normas , Estándares de Referencia , Chile , Peso Fetal , Consenso
3.
Front Med (Lausanne) ; 9: 871903, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35665360

RESUMEN

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominant genetic disorder involving defects in two predominant genes known as endoglin (ENG; HHT-1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT-2). It is characterized by mucocutaneous telangiectases that, due to their fragility, frequently break causing recurrent epistaxis and gastrointestinal bleeding. Because of the severity of hemorrhages, the study of the hemostasis involved in these vascular ruptures is critical to find therapies for this disease. Our results demonstrate that HHT patients with high bleeding, as determined by a high Epistaxis Severity Score (ESS), do not have prolonged clotting times or alterations in clotting factors. Considering that coagulation is only one of the processes involved in hemostasis, the main objective of this study was to investigate the overall mechanisms of hemostasis in HHT-1 (Eng +/-) and HHT-2 (Alk1 +/-) mouse models, which do not show HHT vascular phenotypes in the meaning of spontaneous bleeding. In Eng +/- mice, the results of in vivo and in vitro assays suggest deficient platelet-endothelium interactions that impair a robust and stable thrombus formation. Consequently, the thrombus could be torn off and dragged by the mechanical force exerted by the bloodstream, leading to the reappearance of hemorrhages. In Alk1 +/- mice, an overactivation of the fibrinolysis system was observed. These results support the idea that endoglin and Alk1 haploinsufficiency leads to a common phenotype of impaired hemostasis, but through different mechanisms. This contribution opens new therapeutic approaches to HHT patients' epistaxis.

4.
Int J Mol Sci ; 22(1)2020 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-33375253

RESUMEN

Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed.


Asunto(s)
Endoglina/metabolismo , Retardo del Crecimiento Fetal/patología , Enfermedades Placentarias/patología , Preeclampsia/patología , Trofoblastos/patología , Enfermedades Vasculares/patología , Animales , Endoglina/genética , Femenino , Retardo del Crecimiento Fetal/etiología , Retardo del Crecimiento Fetal/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Enfermedades Placentarias/etiología , Enfermedades Placentarias/metabolismo , Preeclampsia/etiología , Preeclampsia/metabolismo , Embarazo , Trofoblastos/metabolismo , Enfermedades Vasculares/etiología , Enfermedades Vasculares/metabolismo
5.
Cells ; 9(4)2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32316263

RESUMEN

Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased transcript levels of BMP4 in lungs, stomach, and duodenum, and increased circulating levels of BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appeared 18 days after mating, coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 were positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the physiopathology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.


Asunto(s)
Proteína Morfogenética Ósea 4/metabolismo , Endoglina/sangre , Células Endoteliales/metabolismo , Hipertensión/metabolismo , Preeclampsia/sangre , Animales , Proteína Morfogenética Ósea 4/antagonistas & inhibidores , Proteína Morfogenética Ósea 4/genética , Proteínas Portadoras/farmacología , Endoglina/metabolismo , Femenino , Humanos , Hipertensión/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Preeclampsia/fisiopatología , Embarazo , Proteómica , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia Arriba
6.
Toxicol Sci ; 175(1): 75-86, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32110797

RESUMEN

Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted low-molecular weight iron-siderophore-binding protein. NGAL overexpression in injured tubular epithelia partly explains its utility as a sensitive and early urinary biomarker of acute kidney injury (AKI). Herein, we extend mechanistic insights into the source and kinetics of urinary NGAL excretion in experimental AKI. Three models of experimental AKI were undertaken in adult male Wistar rats; renal ischemia-reperfusion injury (IRI) and gentamicin (G) and cisplatin (Cisp) nephrotoxicity. Alongside standard histological and biochemical assessment of AKI, urinary NGAL excretion rate, plasma NGAL concentration, and renal NGAL mRNA/protein expression were assessed. In situ renal perfusion studies were undertaken to discriminate direct shedding of NGAL to the urine from addition of NGAL to the urine secondary to alterations in the tubular handling of glomerular filtrate-derived protein. Renal NGAL expression and urinary excretion increased in experimental AKI. In acute studies in both the IRI and G models, direct renal perfusion with Kreb's buffer eliminated urinary NGAL excretion. Addition of exogenous NGAL to the Kreb's buffer circuit, reestablishment of perfusion with systemic blood or reperfusion with renal vein effluent restored high levels of urinary NGAL excretion. Urinary NGAL excretion in AKI arises in large proportion from reduced reabsorption from the glomerular filtrate. Hence, subclinical cellular dysfunction could increase urinary NGAL, particularly in concert with elevations in circulating prerenal NGAL and/or pharmacological inhibition of tubular reabsorption. More granular interpretation of urinary NGAL measurements could optimize the scope of its clinical utility as a biomarker of AKI.


Asunto(s)
Lesión Renal Aguda/orina , Túbulos Renales/metabolismo , Lipocalina 2/orina , Reabsorción Renal , Daño por Reperfusión/orina , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores/orina , Cisplatino , Modelos Animales de Enfermedad , Gentamicinas , Túbulos Renales/fisiopatología , Lipocalina 2/genética , Masculino , Ratas Wistar , Daño por Reperfusión/etiología , Daño por Reperfusión/genética , Daño por Reperfusión/fisiopatología , Factores de Tiempo , Regulación hacia Arriba
7.
Angiogenesis ; 23(2): 231-247, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31897911

RESUMEN

Endoglin (CD105) is an auxiliary receptor for members of the TFG-ß superfamily. Whereas it has been demonstrated that the deficiency of endoglin leads to minor and defective angiogenesis, little is known about the effect of its increased expression, characteristic of several types of cancer. Angiogenesis is essential for tumor growth, so high levels of proangiogenic molecules, such as endoglin, are supposed to be related to greater tumor growth leading to a poor cancer prognosis. However, we demonstrate here that endoglin overexpression do not stimulate sprouting or vascularization in several in vitro and in vivo models. Instead, steady endoglin overexpression keep endothelial cells in an active phenotype that results in an impairment of the correct stabilization of the endothelium and the recruitment of mural cells. In a context of continuous enhanced angiogenesis, such as in tumors, endoglin overexpression gives rise to altered vessels with an incomplete mural coverage that permit the extravasation of blood. Moreover, these alterations allow the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.


Asunto(s)
Endoglina/genética , Metástasis de la Neoplasia/genética , Neoplasias/irrigación sanguínea , Neoplasias/genética , Neovascularización Patológica/genética , Animales , Movimiento Celular/genética , Células Cultivadas , Endoglina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Invasividad Neoplásica , Neoplasias/patología , Neovascularización Patológica/patología , Regulación hacia Arriba/genética
8.
Toxicol Sci ; 174(1): 3-15, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31825490

RESUMEN

Acute kidney injury (AKI) is a serious syndrome with increasing incidence and health consequences, and high mortality rate among critically ill patients. Acute kidney injury lacks a unified definition, has ambiguous semantic boundaries, and relies on defective diagnosis. This, in part, is due to the absence of biomarkers substratifying AKI patients into pathophysiological categories based on which prognosis can be assigned and clinical treatment differentiated. For instance, AKI involving acute tubular necrosis (ATN) is expected to have a worse prognosis than prerenal, purely hemodynamic AKI. However, no biomarker has been unambiguously associated with tubular cell death or is able to provide etiological distinction. We used a cell-based system to identify TCP1-eta in the culture medium as a noninvasive marker of damaged renal tubular cells. In rat models of AKI, TCP1-eta was increased in the urine co-relating with renal cortical tubule damage. When kidneys from ATN rats were perfused in situ with Krebs-dextran solution, a portion of the urinary TCP1-eta protein content excreted into urine disappeared, and another portion remained within the urine. These results indicated that TCP1-eta was secreted by tubule cells and was not fully reabsorbed by the damaged tubules, both effects contributing to the increased urinary excretion. Urinary TCP1-eta is found in many etiologically heterogeneous AKI patients, and is statistically higher in patients partially recovered from severe AKI. In conclusion, urinary TCP1-eta poses a potential, substratifying biomarker of renal cortical damage associated with bad prognosis.


Asunto(s)
Lesión Renal Aguda/orina , Chaperonina con TCP-1/orina , Túbulos Renales/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Apoptosis , Biomarcadores/orina , Estudios de Casos y Controles , Línea Celular , Modelos Animales de Enfermedad , Diagnóstico Precoz , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Ratas Wistar , Eliminación Renal , Urinálisis
9.
J Clin Med ; 8(12)2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31805674

RESUMEN

Ulcerative colitis is a relatively frequent, chronic disease that impacts significantly the patient's quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental colitis was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Half of the mice received an i.v. dose of CT-1 (200 µg/kg) 2 h before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS administration. The severity of colitis was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF IFN-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before induction of colitis improves the clinical course, tissue damage, and inflammation in DSS-induced colitis in mice.

10.
Acta Physiol (Oxf) ; 226(2): e13247, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30589223

RESUMEN

AIM: Chronic kidney disease is characterized by tubulointerstitial fibrosis involving inflammation, tubular apoptosis, fibroblast proliferation and extracellular matrix accumulation. Cardiotrophin-1, a member of the interleukin-6 family of cytokines, protects several organs from damage by promoting survival and anti-inflammatory effects. However, whether cardiotrophin-1 participates in the response to chronic kidney injury leading to renal fibrosis is unknown. METHODS: We hypothesized and assessed the potential role of cardiotrophin-1 in a mice model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO). RESULTS: Three days after UUO, obstructed kidneys from cardiotrophin-1-/- mice show higher expression of inflammatory markers IL-1ß, Cd68, ICAM-1, COX-2 and iNOs, higher activation of NF-κB, higher amount of myofibroblasts and higher severity of tubular damage and apoptosis, compared with obstructed kidneys from wild-type littermates. In a later stage, obstructed kidneys from cardiotrophin-1-/- mice show higher fibrosis than obstructed kidneys from wild-type mice. Interestingly, administration of exogenous cardiotrophin-1 prevents the increased fibrosis resulting from the genetic knockout of cardiotrophin-1 upon UUO, and supplementation of wild-type mice with exogenous cardiotrophin-1 further reduces the renal fibrosis induced by UUO. In vitro, renal myofibroblasts from cardiotrophin-1-/- mice have higher collagen I and fibronectin expression and higher NF-κB activation than wild-type cells. CONCLUSIONS: Cardiotrophin-1 participates in the endogenous response that opposes renal damage by counteracting the inflammatory, apoptotic and fibrotic processes. And exogenous cardiotrophin-1 is proposed as a candidate for the treatment and prevention of chronic renal fibrosis.


Asunto(s)
Citocinas/metabolismo , Fibrosis/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Obstrucción Ureteral/metabolismo , Animales , Citocinas/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/fisiología , Ratones Noqueados , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Obstrucción Ureteral/genética
11.
Transplantation ; 102(10): e404-e412, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30247450

RESUMEN

BACKGROUND: Cold ischemia-reperfusion injury is unavoidable during organ transplantation, and prolonged preservation is associated with poorer function recovery. Cardiotrophin-1 (CT-1) is an IL-6 family cytokine with cytoprotective properties. This preclinical study in rats tested whether CT-1 mitigates cold renal ischemia-reperfusion injury in the context of the transplantation of long-time preserved kidneys. METHODS: Kidneys were flushed with cold (4°C) University of Wisconsin solution containing 0.2 µg/mL CT-1 and stored for several periods of time at 4°C in the same solution. In a second approach, kidneys were first cold-preserved for 6 hours and then were perfused with University of Wisconsin solution containing CT-1 (0, 16, 32, or 64 µg/mL) and further cold-preserved. Organ damage markers were measured in the kidneys at the end of the storage period. For renal transplantation, recipient consanguineous Fischer rats underwent bilateral nephrectomy and received a previously cold-preserved (24 hours) kidney as described above. Survival and creatinine clearance were monitored over 30 days. RESULTS: Cardiotrophin-1 in perfusion and preservation fluids reduced oxidative stress markers (superoxide anion and inducible nitric oxide synthase), inflammation markers (NF-κB and tumor necrosis factor-α), and vascular damage (vascular cell adhesion molecule-1) and activated leukemia inhibitory factor receptor and STAT-3 survival signaling. Transplantation of kidneys cold-preserved with CT-1 increased rat survival and renal function (ie, lower plasma creatinine and higher creatinine clearance) and improved kidney damage markers after transplantation (ie, lower superoxide anion, tumor necrosis factor-α, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and higher NF-κB). CONCLUSIONS: Cardiotrophin-1 represents a novel therapeutic strategy to reduce ischemia-reperfusion and cold preservation injury to rescue suboptimal kidneys and, consequently, to improve the clinical outcomes of renal transplantation.


Asunto(s)
Citocinas/uso terapéutico , Trasplante de Riñón/efectos adversos , Preservación de Órganos/métodos , Daño por Reperfusión/prevención & control , Recolección de Tejidos y Órganos/métodos , Adenosina/química , Aloinjertos/irrigación sanguínea , Aloinjertos/efectos de los fármacos , Alopurinol/química , Animales , Isquemia Fría/efectos adversos , Citocinas/farmacología , Modelos Animales de Enfermedad , Glutatión/química , Supervivencia de Injerto/efectos de los fármacos , Humanos , Insulina/química , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Pruebas de Función Renal , Trasplante de Riñón/métodos , Masculino , Nefrectomía , Soluciones Preservantes de Órganos/química , Perfusión/métodos , Rafinosa/química , Ratas , Ratas Endogámicas F344 , Daño por Reperfusión/etiología , Recolección de Tejidos y Órganos/efectos adversos
13.
Toxicol Appl Pharmacol ; 349: 83-93, 2018 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-29679655

RESUMEN

Nephrotoxicity is the main limitation to the dosage and anticancer efficacy of cisplatin. Cisplatin produces tubular epithelial cell apoptosis and necrosis depending on the concentration of the drug. Protection from cisplatin nephrotoxicity must therefore tackle both cell death modes. For its ability to reduce cisplatin reactivity, in addition to its antioxidant effect, we tested and found that N-acetylcysteine (NAC) was most effective at inhibiting cisplatin cytotoxicity. NAC has no significant effect on cell death induced by either cycloheximide or Fas activation, indicating a rather selective action. Pt-DNA-binding experiments suggest that the differential effectiveness of NAC is due to its capacity to quench cisplatin reactivity inside the cell. NAC abolishes cisplatin-induced apoptosis, and transforms the necrosis induced by high concentrations of cisplatin into apoptosis. In fact, NAC allows the anti-apoptotic molecule Bcl-2 to reduce the cell death caused by pro-necrotic concentrations of cisplatin, to a significantly greater extent than in the absence of NAC. In rats, a dosage of NAC that significantly ameliorates cisplatin nephrotoxicity, has little effect on gentamicin nephrotoxicity. These characteristics provide NAC with a rationale as a potential nephroprotectant specifically tailored to and especially effective for therapeutic courses with platinated antineoplastics, which prompts to deepening into further preclinical knowledge, and to initiate clinical studies with NAC and mixed therapies composed of NAC and antiapoptotic drugs.


Asunto(s)
Acetilcisteína/farmacología , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Cisplatino/toxicidad , Depuradores de Radicales Libres/farmacología , Necrosis/inducido químicamente , Animales , Caspasas/análisis , Caspasas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Células Jurkat , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Wistar
14.
Clin Sci (Lond) ; 132(9): 985-1001, 2018 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-29572384

RESUMEN

Cardiotrophin-1 (CT-1) holds potent anti-inflammatory, cytoprotective, and anti-apoptotic effects in the liver, kidneys, and heart. In the present study, the role of endogenous CT-1 and the effect of exogenous CT-1 were evaluated in experimental ulcerative colitis. Colitis was induced in CT-1 knockout and wild-type (WT) mice by administration of dextran sulphate sodium (DSS) in the drinking water during 7 days. CT-1 knockout mice showed higher colon damage and disease severity than WT mice. In addition, CT-1 (200 µg/kg/day, iv) or vehicle (as control) was administered during 3 days to WT, colitic mice, starting on day 4 after initiation of DSS. Disease activity index (DAI), inflammatory markers (tumor necrosis factor α (TNF-α), INFγ, IL-17, IL-10, inducible nitric oxide synthase (iNOS)), colon damage, apoptosis (cleaved caspase 3), nuclear factor κB (NFκB) and STAT-3 activation, and bacterial translocation were measured. Compared with mice treated with DSS, mice also treated with exogenous CT-1 showed lower colon damage, DAI, plasma levels of TNFα, colon expression of TNF-α, INFγ, IL-17, iNOS and cleaved caspase 3, higher NFκB and signal transducer and activator of transcription 3 (STAT3) pathways activation, and absence of bacterial translocation. We conclude that endogenous CT-1 plays a role in the defense and repair response of the colon against ulcerative lesions through an anti-inflammatory and anti-apoptotic effect. Supplementation with exogenous CT-1 ameliorates disease symptoms, which opens a potentially new therapeutic strategy for ulcerative colitis.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Citocinas/sangre , Citocinas/uso terapéutico , Animales , Colitis Ulcerosa/inducido químicamente , Citocinas/genética , Sulfato de Dextran , Evaluación Preclínica de Medicamentos , Masculino , Ratones , Ratones Noqueados
15.
J Cell Mol Med ; 22(1): 302-314, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28857467

RESUMEN

Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF-2α protein decreased, whereas focal adhesion kinase protein (FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV. Proteasome inhibition or FAK inactivation in cells plated on collagen I restored erythropoietin and HIF-2α expression. FAK inhibition also decreased the collagen I-dependent proteasome activation. In a model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice, increased collagen I protein content and an almost complete disappearance of erythropoietin mRNA expression were observed in the ureteral ligated kidney with respect to the contralateral control. Interestingly, erythropoietin synthesis was recovered in obstructed mice treated with proteasome inhibitor. These data suggest that reduced kidney erythropoietin synthesis could be caused by the accumulation of abnormal extracellular matrix proteins.


Asunto(s)
Eritropoyetina/biosíntesis , Matriz Extracelular/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular , Colágeno Tipo I/farmacología , Regulación hacia Abajo/efectos de los fármacos , Eritropoyetina/genética , Eritropoyetina/metabolismo , Matriz Extracelular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Riñón/patología , Ratones Endogámicos C57BL , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Proteolisis/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Insuficiencia Renal Crónica/patología , Obstrucción Ureteral/patología
16.
Cell Mol Life Sci ; 75(7): 1269-1284, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29080903

RESUMEN

Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also, platelets adhere to confluent endothelial cells in an endoglin-mediated process. Remarkably, Chinese hamster ovary cells ectopically expressing the human αIIbß3 integrin acquire the capacity to adhere to myoblast transfectants expressing human endoglin, whereas platelets from Glanzmann's thrombasthenia patients lacking the αIIbß3 integrin are defective for endoglin-dependent adhesion to endothelial cells. Furthermore, the bleeding time, but not the prothrombin time, is significantly prolonged in endoglin-haplodeficient (Eng +/-) mice compared to Eng +/+ animals. These results suggest a new role for endoglin in αIIbß3 integrin-mediated adhesion of platelets to the endothelium, and may provide a better understanding on the basic cellular mechanisms involved in hemostasis and thrombo-inflammatory events.


Asunto(s)
Plaquetas/metabolismo , Comunicación Celular , Endoglina/metabolismo , Células Endoteliales/metabolismo , Animales , Plaquetas/citología , Células CHO , Adhesión Celular , Línea Celular , Células Cultivadas , Cricetinae , Cricetulus , Endoglina/genética , Células Endoteliales/citología , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/genética , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo
17.
Food Chem Toxicol ; 107(Pt A): 226-236, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28669851

RESUMEN

Strategies to minimize the nephrotoxicity of platinated antineoplastics without affecting its antitumour efficacy are strongly necessary to improve the pharmacotoxicological profile of these drugs. The natural flavonoid quercetin has been shown to afford nephroprotection without affecting cisplatin antitumour effect. The purpose of the present study has been to assess the differential mechanisms of action of cisplatin and quercetin on kidney and tumour tissues that could explain these effects. Wistar rats bearing subcutaneous tumours were treated with cisplatin and quercetin (and the appropriate controls). Tumour size and renal function evolution was monitored during 6 days. Platinum and quercetin content were also determined in both tissues. All the parameters studied, including blood supply, inflammation, apoptosis, critical MAPK signaling and oxidative stress in the cisplatin-treated animals are almost normalized by quercetin in the kidneys, but unaffected in the tumours. Our results suggest that in a cancer model in vivo, the protection exerted by quercetin on cisplatin nephrotoxicity is related to its antioxidant, vascular, anti-inflammatory and antiapoptotic effects, but these properties do not affect the mechanisms responsible for the antitumour effect of cisplatin.


Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Neoplasias Renales/tratamiento farmacológico , Quercetina/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Antioxidantes/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/administración & dosificación , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Neoplasias Renales/metabolismo , Neoplasias Renales/fisiopatología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Ratas Wistar
18.
Expert Opin Biol Ther ; 17(9): 1053-1063, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28656781

RESUMEN

INTRODUCTION: Alterations in the process of angiogenesis, either by excess or by defect, are present in different common pathologies. For this reason, great efforts are being made toward the development of pro- and anti-angiogenic therapies. Since endoglin levels are enhanced in tissues undergoing angiogenesis, and changes in its expression lead to alterations in vessel formation, endoglin has become an ideal target for these types of therapies. Areas covered: In this review, the role of endoglin in angiogenesis is summarized. In addition, the authors review pro- and anti-angiogenic therapies that are currently being used and new approaches that target endoglin. The article includes therapies that are both in preclinical and clinical development. Expert opinion: Endoglin is a very good target for anti-angiogenic therapy, as demonstrated by the positive results obtained with anti-endoglin antibodies. However, although endoglin in pro-angiogenic therapies has been successful in vitro, its use has not yet reached clinical settings. Moreover, the authors believe that establishing the exact role of endoglin in angiogenesis is essential and that this should be the next step in this field in the coming years.


Asunto(s)
Endoglina/metabolismo , Neoplasias/terapia , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Malformaciones Arteriovenosas/patología , Malformaciones Arteriovenosas/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Endoglina/antagonistas & inhibidores , Terapia Genética , Humanos , Inmunoterapia , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica , Transducción de Señal/efectos de los fármacos
19.
Sci Rep ; 7: 41875, 2017 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-28157227

RESUMEN

Hypertension, diabetes and obesity are cardiovascular risk factors closely associated to the development of renal and cardiovascular target organ damage. VAV2 and VAV3, members of the VAV family proto-oncogenes, are guanosine nucleotide exchange factors for the Rho and Rac GTPase family, which is related with cardiovascular homeostasis. We have analyzed the relationship between the presence of VAV2 rs602990 and VAV3 rs7528153 polymorphisms with cardiovascular risk factors and target organ damage (heart, vessels and kidney) in 411 subjects. Our results show that being carrier of the T allele in VAV2 rs602990 polymorphism is associated with an increased risk of obesity, reduced levels of ankle-brachial index and diastolic blood pressure and reduced retinal artery caliber. In addition, being carrier of T allele is associated with increased risk of target organ damage in males. On the other hand, being carrier of the T allele in VAV3 rs7528153 polymorphism is associated with a decreased susceptibility of developing a pathologic state composed by the presence of hypertension, diabetes, obesity or cardiovascular damage, and with an increased risk of developing altered basal glycaemia. This is the first report showing an association between VAV2 and VAV3 polymorphisms with cardiovascular risk factors and target organ damage.


Asunto(s)
Enfermedades Cardiovasculares/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-vav/genética , Adulto , Anciano , Anciano de 80 o más Años , Índice Tobillo Braquial , Glucemia/metabolismo , Presión Sanguínea , Peso Corporal , Enfermedades Cardiovasculares/patología , Estudios de Casos y Controles , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Arteria Retiniana/patología , Factores Sexuales
20.
Angiogenesis ; 20(1): 1-24, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27943030

RESUMEN

Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by reorganizing preexisting capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling preexisting collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of endoglin in post-occlusion reperfusion is sustained by several observations: (1) endoglin expression is increased in vessels showing active angiogenesis/remodeling; (2) genetic endoglin haploinsufficiency in humans causes deficient angiogenesis; and (3) the reduction of endoglin expression by gene disruption or the administration of endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of endoglin in several phenomena (angiogenesis, arteriogenesis and collateral development) associated with post-ischemic revascularization.


Asunto(s)
Endoglina/metabolismo , Isquemia/metabolismo , Isquemia/fisiopatología , Neovascularización Fisiológica , Animales , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Transducción de Señal , Remodelación Vascular
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