Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
J Med Chem ; 63(5): 2263-2281, 2020 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-31589043

RESUMEN

ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid ß (Aß) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aß40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ciclopropanos/farmacología , Inhibidores Enzimáticos/farmacología , Tiazinas/farmacología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Masculino , Ratones , Modelos Moleculares , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/metabolismo , Ratas Sprague-Dawley , Tiazinas/química , Tiazinas/farmacocinética , Tiazinas/uso terapéutico
2.
Oxid Med Cell Longev ; 2013: 628615, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23476722

RESUMEN

This laboratory previously identified an albumin-like protein (denoted as p70) as a component of the macromolecular complex assembled within the 5'-regulatory region of redox-sensitive genes in vascular smooth muscle cells (vSMCs). Here we show that p70 is present in the cytosolic and nuclear compartments of vSMCs and dynamically responsive to redox status. Intense cytoplasmic and perinuclear staining, coupled with enhanced nuclear localization, was observed in vSMCs, but not HepG2 cells, treated with benzo(a)pyrene (BaP), H(2)O(2), or N-acetylcysteine, agents known to modulate redox status. 3' RACE indicated that p70 is not generated as a product of endogenous gene expression, but rather taken up from the extracellular compartment. While p70 was undetectable in cells grown for 24 hours under serum-free conditions, cell-associated, acid-resistant albumin was detected 30 min after the addition of exogenous albumin. vSMCs incubated at 4°C with 100 µ g/mL unlabeled BSA and 10 µ g/mL FITC-BSA for 60 minutes and switched to 37°C to examine temperature-sensitive label uptake showed punctate structures throughout the cell consistent with albumin internalization at the higher temperature. Albumin was found to influence redox-signaling, as evidenced by modulation of cyp1a1 gsta1 and Ha-ras gene inducibility. Together, these results implicate albumin and albumin-like proteins as critical regulators of vascular redox signaling.


Asunto(s)
Músculo Liso Vascular/metabolismo , Proteínas/metabolismo , Acetilcisteína/toxicidad , Albúminas/metabolismo , Secuencia de Aminoácidos , Animales , Benzo(a)pireno/toxicidad , Células COS , Células Cultivadas , Chlorocebus aethiops , Fluoresceína-5-Isotiocianato/química , Células HEK293 , Células Hep G2 , Humanos , Peróxido de Hidrógeno/toxicidad , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Músculo Liso Vascular/citología , Oxidación-Reducción , Transducción de Señal/efectos de los fármacos
3.
Mol Med ; 17(11-12): 1275-84, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21863216

RESUMEN

Mounting evidence suggests that the blueprint of chronic renal disease is established during early development by environmental cues that dictate alterations in differentiation programming. Here we show that aryl hydrocarbon receptor (AHR), a lig-and-activated basic helix-loop-helix-PAS homology domain transcription factor, disrupts murine renal differentiation by interfering with Wilms tumor suppressor gene (WT1) signaling in the developing kidney. Embryonic kidneys of C57BL/6J Ahr⁻/⁻ mice at gestation d (GD) 14 showed reduced condensation in the nephrogenic zone and decreased numbers of differentiated structures compared with wild-type mice. These deficits correlated with increased expression of the (+) 17aa Wt1 splice variant, decreased mRNA levels of Igf-1 rec., Wnt-4 and E-cadherin, and reduced levels of 52 kDa WT1 protein. AHR knockdown in wild-type embryonic kidney cells mimicked these alterations with notable increases in (+) 17aa Wt1 mRNA, reduced levels of 52 kDa WT1 protein, and increased (+) 17aa 40-kDa protein. AHR downregulation also reduced Igf-1 rec., Wnt-4, secreted frizzled receptor binding protein-1 (sfrbp-1) and E-cadherin mRNAs. In the case of Igf-1 rec. and Wnt-4, genetic disruption was fully reversed upon restoration of cellular Wt1 protein levels, confirming that functional interactions between AHR and Wt1 represent a likely molecular target for renal developmental interference.


Asunto(s)
Reprogramación Celular/genética , Riñón/embriología , Organogénesis/genética , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas WT1/genética , Animales , Diferenciación Celular , Línea Celular , Regulación hacia Abajo/genética , Epitelio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Riñón/citología , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Transporte de Proteínas , ARN Interferente Pequeño/metabolismo , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Proteínas WT1/metabolismo
4.
Environ Health Perspect ; 119(12): 1745-53, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21803694

RESUMEN

BACKGROUND: The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis. OBJECTIVES: We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP). METHODS: We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahr(b-1) allele and B6.D2N-Ahr(d)/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahr(d)) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis. RESULTS: Hydrocarbon challenge of metanephri from C57 mice altered Wilms' tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10-13. CONCLUSIONS: These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Benzo(a)pireno/toxicidad , Regulación del Desarrollo de la Expresión Génica/genética , Riñón/embriología , Exposición Materna/efectos adversos , Morfogénesis/efectos de los fármacos , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Análisis de Varianza , Animales , Benzo(a)pireno/metabolismo , Western Blotting , Células Cultivadas , Cartilla de ADN/genética , Receptores ErbB/metabolismo , Femenino , Técnicas Histológicas , Inmunohistoquímica , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción PAX2/metabolismo , Reacción en Cadena de la Polimerasa , Embarazo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Sindecano-1/metabolismo , Proteínas WT1/genética , Proteínas WT1/metabolismo
5.
Birth Defects Res A Clin Mol Teratol ; 91(8): 693-702, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21384534

RESUMEN

BACKGROUND: L1 retroelements may play a central role in morphogenesis through epigenetic mechanisms involving recruitment of chromatin modifying protein complexes. Retroelements are repressed in terminally differentiated cells, and highly active in embryonic, undifferentiated, and transformed cells. It is not clear if the modulation of differentiation by L1 is a "cause" or "effect". The purpose of this study was to determine if murine embryonic kidney cells of clonal origin (mK4 cells) harbor retrotransposition events upon ectopic expression of L1, and the impact of L1 on embryonic kidney cell differentiation. Given that L1 is reactivated by aryl hydrocarbon receptor (AHR) ligands, we also sought to investigate the effects of benzo(a)pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the genetic network of mK4 cells. METHODS: The mK4 cells overexpressing human L1(RP) were assessed for changes in proliferation and expression of molecular markers of cellular differentiation. RESULTS: L1(RP) increased proliferation rates and markedly downregulated differentiation programming in mK4 cells. These genetic alterations were recapitulated by exogenous activation of L1 by AHR ligands. CONCLUSION: L1 regulates nephrogenesis in vitro via both insertional and non-insertional mechanisms that disrupt mesenchymal to epithelial transition. Thus, a feedback loop involving L1, WT1, and AHR may play a role in regulation of kidney morphogenesis. Birth Defects Research (Part A), 2011. © 2011 Wiley-Liss, Inc.


Asunto(s)
Diferenciación Celular , Epigénesis Genética , Regulación del Desarrollo de la Expresión Génica , Riñón/embriología , Retroelementos/efectos de los fármacos , Animales , Benzo(a)pireno/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Riñón/citología , Riñón/metabolismo , Ratones , Morfogénesis/efectos de los fármacos , Dibenzodioxinas Policloradas/farmacología , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo
6.
Proc Natl Acad Sci U S A ; 107(9): 4153-8, 2010 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-20160076

RESUMEN

Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adenilato Quinasa/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Línea Celular , Proteínas de Unión al ADN/genética , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Transgénicos , Complejos Multiproteicos , Estrés Oxidativo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas , Serina-Treonina Quinasas TOR , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética
7.
Birth Defects Res C Embryo Today ; 87(2): 192-7, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19530133

RESUMEN

Recent studies have identified AHR as a master regulator of Wilms' tumor suppressor gene (WT1) signaling in the developing kidney. Activation of AHR signaling by environmental chemical is associated with proteasome-mediated degradation of AHR protein, disruption of WT1 alternative splicing, and marked alterations in the regulation of genetic programs of developmental progression in the developing kidney. The complexity of genetic regulatory networks of nephrogenesis controlled by AHR-WT1 interactions will be discussed here with particular emphasis given to the biological and medical consequences that may result from deficits in nephrogenesis that compromise reserve capacity and renal function later in life. Understanding the impact of early-life environmental exposures to chemicals that disrupt AHR signaling can help minimize negative health consequences to pregnant women and their offspring.


Asunto(s)
Benzo(a)pireno/toxicidad , Carcinógenos/toxicidad , Regulación del Desarrollo de la Expresión Génica/genética , Redes Reguladoras de Genes , Riñón/embriología , Proteínas WT1/genética , Adulto , Empalme Alternativo/efectos de los fármacos , Empalme Alternativo/genética , Animales , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Ratones , Ratones Noqueados , Morfogénesis , Embarazo , Ratas , Receptor Cross-Talk/efectos de los fármacos , Receptor Cross-Talk/fisiología , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas WT1/efectos de los fármacos , Adulto Joven
8.
Cell Stress Chaperones ; 12(3): 209-18, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17915553

RESUMEN

Environmental injury has been associated with endoplasmic reticulum (ER) stress, a response characterized by activation of the unfolded protein response, proteasomal degradation of proteins, and induction of HSPA5, also known as GRP78 or BiP. Although HSPA5 has been implicated in the stress response to environmental injury in several cell types, its role in the glomerular ER stress response is unknown. In this study, we evaluated HSPA5 activation profiles in rat glomerular mesangial cells (rGMCs) challenged with heavy metals (HgCl2 or Pb2+ acetate) or polycyclic aromatic hydrocarbons (PAHs, ie, benzo(a)pyrene [BaP]). Challenge of rGMCs with 1 or 10 microM HgCl2 or Pb2+ acetate increased HSPA5 mRNA and protein levels. The induction response was sensitive to transcriptional and translational inhibition by actinomycin D (AD) and cyclohexamide, respectively. HSPA5 mRNA was induced by 3 microM BaP in an AD-sensitive manner, but this response was unaffected by the presence of heavy metals. A promoter construct containing sequences that mediate thapsigargin (TH) inducibility of the HSPA5 promoter was refractory to both heavy metals and BaP. The HSPA5 induction response in rGMCs is conserved because it was reproduced with fidelity in immunolocalization experiments of HSPA5 protein in M15 and HEK293 cells in embryonic lines of murine and human origin, respectively. Collectively, these findings identify HSPA5 in the stress response of rGMCs and implicate regulatory mechanisms that are distinct from those involved in TH inducibility.


Asunto(s)
Benzo(a)pireno/toxicidad , Retículo Endoplásmico/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Cloruro de Mercurio/toxicidad , Células Mesangiales/efectos de los fármacos , Chaperonas Moleculares/metabolismo , Compuestos Organometálicos/toxicidad , Estrés Fisiológico/metabolismo , Animales , Línea Celular , Cicloheximida/farmacología , Dactinomicina/farmacología , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/genética , Humanos , Células Mesangiales/metabolismo , Ratones , Chaperonas Moleculares/genética , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Regiones Promotoras Genéticas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Procesamiento Postranscripcional del ARN/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Estrés Fisiológico/genética , Tapsigargina/farmacología , Transcripción Genética/efectos de los fármacos , Transfección
9.
Environ Mol Mutagen ; 48(5): 395-9, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17567845

RESUMEN

As the postgenomic era continues to unfold, a new wave of scientific investigation is upon us focusing on the application of genomic technologies to study the meanings encrypted on the DNA code and the responses of living organisms to changes in their environment. Recent functional genomics studies in this laboratory have focused on the role of the aryl hydrocarbon receptor, a ubiquitous transcription factor, in genetic programming during renal development. Also of interest is the application of genomics investigations to the study of chronic medical conditions associated with early life exposures to environmental contaminants. Molecular evidence is discussed in this review within the framework of human molecular medicine.


Asunto(s)
Genómica/métodos , Receptores de Hidrocarburo de Aril/fisiología , Animales , Benzo(a)pireno/farmacología , Contaminación Ambiental/análisis , Contaminación Ambiental/prevención & control , Expresión Génica/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas WT1/genética , Proteínas WT1/metabolismo , Proteínas WT1/fisiología
10.
Thromb Haemost ; 97(4): 587-97, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17393022

RESUMEN

The plasma membrane Ca(2+)-ATPase (PMCA) plays an essential role in maintaining low cytosolic Ca(2+) in resting platelets. Earlier studies demonstrated that the 4b isoform of PMCA interacts via its C-terminal end with the PDZ domains of membrane-associated guanylate kinase proteins. Activation of saponin-permeabilized platelets in the presence of a peptide composed of the last ten residues of the PMCA4b C-terminus leads to a significant decrease of PMCA associated with the cytoskeleton, suggesting that PDZ domain interactions play a role in tethering the pump to the cytoskeleton. Here we present experiments conducted to evaluate the mechanism of this association. Co-immunoprecipitation assays coupled with liquid chromatography/tandem mass spectrometry analysis and immunoblotting were used to identify proteins that interact with PMCA in the resting platelet. Our results indicate that the only PDZ domain-containing protein associated with PMCA is the LIM family protein, CLP36. Glutathione-S-transferase pull-down from a platelet extract using a fusion protein containing the C-terminal PDZ domain binding motif of PMCA confirmed binding of CLP36 to PMCA. Gel filtration chromatography of detergent-solubilized platelets demonstrated the existence of a 1,000-kDa complex containing PMCA and CLP36, and in addition, alpha-actinin and actin. Immunoflourescence microscopy confirmed the co-localization of PMCA with CLP36 in resting and activated platelets. Taken together these results suggest that PMCA is localized in non-filamentous actin complexes in resting platelets by means of PDZ domain interactions and then associates with the actin cytoskeleton during cytoskeletal rearrangement upon platelet activation. Thus, in addition to the reversible serine/threonine and tyrosine phosphorylation events previously described in human platelets, PMCA function may be regulated by interactions with anchoring and cytoskeletal proteins.


Asunto(s)
Actinina/metabolismo , Actinas/metabolismo , Plaquetas/metabolismo , Citoesqueleto/metabolismo , Proteínas de Microfilamentos/metabolismo , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo , Activación Plaquetaria , Plaquetas/efectos de los fármacos , Señalización del Calcio , Cromatografía en Gel , Cromatografía Liquida , Humanos , Immunoblotting , Inmunoprecipitación , Técnicas In Vitro , Proteínas con Dominio LIM , Microscopía Confocal , Activación Plaquetaria/efectos de los fármacos , Unión Proteica , Transporte de Proteínas , Seudópodos/metabolismo , Espectrometría de Masas en Tándem , Trombina/farmacología , Factores de Transcripción
11.
Drug Metab Rev ; 38(4): 677-83, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17145695

RESUMEN

Mesenchymal-to-epithelial transition is an important biological event during the course of renal cell differentiation as condensing mesenchyme gives rise to tubuloepithelial structures. Wilms' tumor suppressor gene (Wt1) has been identified as a master regulator of the complex genetic events that mediate mesenchymal transdifferentiation. Evidence is summarized here showing that the tightly regulated series of genetic and biochemical events during nephrogenesis is disrupted by superactivation of aryl hydrocarbon receptor (Ahr) by benzo(a)pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon and renal carcinogen (Falahatpisheh and Ramos, 2003). Nephron formation is inhibited by BaP, a response that involves inhibition of metanephric cell differentiation and shifts in the relative abundance of Wt1 splice variants. A systems biology paradigm that combined approaches from genomics, transcriptomics, and bioinformatics revealed that the global response of murine metanephric cultures to BaP involves downregulation of Ahr and disruption of downstream targets of Wt1. Discrete networks of genetic regulation were resolved using Boolean idealizations and included genes involved in renal cell differentiation and metabolic control. This work has established a role for Ahr in renal cell differentiation and kidney development and resolved putative molecular interactions between Ahr and Wt1.


Asunto(s)
Riñón/embriología , Nefronas/embriología , Animales , Células Epiteliales/fisiología , Femenino , Genes del Tumor de Wilms/fisiología , Humanos , Células Madre Mesenquimatosas/fisiología , Embarazo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/fisiología
12.
Am J Physiol Renal Physiol ; 289(6): F1291-303, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15998846

RESUMEN

Environmental chemicals play an etiological role in greater than 50% of idiopathic glomerular diseases. The present studies were conducted to define mechanisms of renal cell-specific hydrocarbon injury. Female rats were given 10 mg/kg benzo(a)pyrene (BaP) once a week for 16 wk. Progressive elevations in total urinary protein, protein/creatinine ratios, and microalbuminuria were observed in rats treated with BaP for up to 16 wk. The nephropathic response involved early reductions in mesangial cell numbers and fibronectin levels by 8 wk, coupled to transient increases in podocyte cellularity. Changes in podocyte numbers subsided by 16 wk and correlated with rebound increases in mesangial cell numbers and fibronectin levels, along with increased alpha-smooth muscle actin and Cu/Zn superoxide dismutase and fusion of podocyte foot processes. In culture, mesangial cells were more sensitive than podocytes to hydrocarbon injury and expressed higher levels of inducible aryl hydrocarbon hydroxylase activity. Naïve mesangial cells exerted a strong inhibitory influence on podocyte proliferation under both direct and indirect coculture conditions, and this response involved a mesangial cell-derived matrix that selectively inhibited podocyte proliferation. These findings indicate that hydrocarbon nephropathy in rats involves disruption of glomerular cell-cell and cell-matrix interactions mediated by deposition of a mesangial cell-derived growth-inhibitory matrix that regulates podocyte proliferation.


Asunto(s)
Comunicación Celular/fisiología , Glomerulonefritis/fisiopatología , Glomérulos Renales/citología , Animales , Benzo(a)pireno , Sistema Enzimático del Citocromo P-450/biosíntesis , Femenino , Glomerulonefritis/inducido químicamente , Inmunohistoquímica , Glomérulos Renales/patología , Ratas , Ratas Sprague-Dawley
13.
Toxicol Lett ; 139(1): 1-10, 2003 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-12595153

RESUMEN

We have previously reported that the Fas/Apo-1/CD95-mediated apoptosis-inducing signaling system participates in the initiation of toxicant-induced testicular germ cell apoptosis. The contribution of Fas-mediated signaling is especially evident in the initiation of germ cell apoptosis after mono-(2-ethylhexyl)phthalate (MEHP)-induced Sertoli cell injury. In previous work, we demonstrated that the incidence of germ cell apoptosis after MEHP exposure is significantly reduced in B6.SMNC3H-Fas(gld,gld) (gld) mice that express a dysfunctional form of the FasL protein (the associated ligand that activates Fas). This has led to the hypothesis that activation of the Fas-mediated signaling pathway is a common mechanism for the initiation of germ cell apoptosis after toxicant-induced Sertoli cell injury. To test this hypothesis, we evaluated the sensitivity of testicular germ cells of wild-type, gld- and Fas-deficient CBA/KlJms-Tnfrsf6lpr-cg((lpr-cg)) (lpr(cg)) mice to undergo apoptosis after exposure to the Sertoli cell toxicant nitrobenzene (NB). Adult, 8-week-old gld mice treated with a single oral dose of NB (800 mg/kg) were observed to have a higher apoptotic index (AI; 66.1+/-1.3) 24 h after exposure as compared with the wild-type C57BL/6 (C57) mice (50.4+/-1.8). Similarly, 8-week-old lpr(cg) mice treated with NB displayed a higher AI 24 h after exposure (45.1+/-4.6) as compared with the wild-type CBA/KlJms (CBA) mice (32.1+/-3.8). Interestingly, exposure of both peri-pubertal 4-week-old C57 and gld mice showed a similar increase in the incidence of germ cell apoptosis after NB (600 mg/kg) exposure. Taken together, these findings indicate that Fas-mediated signaling is not required for NB-induced germ cell apoptosis and imply that a dysfunctional Fas signaling system sensitizes adult mice to NB-induced germ cell elimination.


Asunto(s)
Apoptosis/efectos de los fármacos , Dietilhexil Ftalato/análogos & derivados , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/metabolismo , Nitrobencenos/farmacología , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Receptor fas/metabolismo , Envejecimiento , Animales , Dietilhexil Ftalato/farmacología , Proteína Ligando Fas , Eliminación de Gen , Regulación de la Expresión Génica , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Nitrobencenos/toxicidad , Células de Sertoli/efectos de los fármacos , Células de Sertoli/patología , Transducción de Señal , Espermatozoides/patología , Testículo/patología , Receptor fas/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA