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1.
Nat Genet ; 51(9): 1369-1379, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31477927

RESUMEN

Promoters and enhancers are key cis-regulatory elements, but how they operate to generate cell type-specific transcriptomes is not fully understood. We developed a simple and robust method, native elongating transcript-cap analysis of gene expression (NET-CAGE), to sensitively detect 5' ends of nascent RNAs in diverse cells and tissues, including unstable transcripts such as enhancer-derived RNAs. We studied RNA synthesis and degradation at the transcription start site level, characterizing the impact of differential promoter usage on transcript stability. We quantified transcription from cis-regulatory elements without the influence of RNA turnover, and show that enhancer-promoter pairs are generally activated simultaneously on stimulation. By integrating NET-CAGE data with chromatin interaction maps, we show that cis-regulatory elements are topologically connected according to their cell type specificity. We identified new enhancers with high sensitivity, and delineated primary locations of transcription within super-enhancers. Our NET-CAGE dataset derived from human and mouse cells expands the FANTOM5 atlas of transcribed enhancers, with broad applicability to biomedical research.


Asunto(s)
Regiones no Traducidas 5'/genética , Biología Computacional/métodos , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Regiones Promotoras Genéticas , ARN/genética , Transcripción Genética , Perfilación de la Expresión Génica , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Sitio de Iniciación de la Transcripción , Transcriptoma
2.
Nucleic Acids Res ; 47(16): 8838-8859, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31329944

RESUMEN

Regnase-1-mediated mRNA decay (RMD), in which inflammatory mRNAs harboring specific stem-loop structures are degraded, is a critical part of proper immune homeostasis. Prior to initial translation, Regnase-1 associates with target stem-loops but does not carry out endoribonucleolytic cleavage. Single molecule imaging revealed that UPF1 is required to first unwind the stem-loops, thus licensing Regnase-1 to proceed with RNA degradation. Following translation, Regnase-1 physically associates with UPF1 using two distinct points of interaction: The Regnase-1 RNase domain binds to SMG1-phosphorylated residue T28 in UPF1; in addition, an intrinsically disordered segment in Regnase-1 binds to the UPF1 RecA domain, enhancing the helicase activity of UPF1. The SMG1-UPF1-Regnase-1 axis targets pioneer rounds of translation and is critical for rapid resolution of inflammation through restriction of the number of proteins translated by a given mRNA. Furthermore, small-molecule inhibition of SMG1 prevents RNA unwinding in dendritic cells, allowing post-transcriptional control of innate immune responses.


Asunto(s)
Macrófagos Peritoneales/inmunología , Degradación de ARNm Mediada por Codón sin Sentido/inmunología , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/genética , Ribonucleasas/genética , Transactivadores/genética , Animales , Fibroblastos/citología , Fibroblastos/inmunología , Células HEK293 , Células HeLa , Homeostasis/genética , Homeostasis/inmunología , Humanos , Inmunidad Innata , Inflamación , Secuencias Invertidas Repetidas , Macrófagos/citología , Macrófagos/inmunología , Macrófagos Peritoneales/citología , Ratones , Ratones Noqueados , Mutación , Cultivo Primario de Células , Unión Proteica , Biosíntesis de Proteínas , Dominios y Motivos de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/inmunología , ARN Mensajero/metabolismo , Ribonucleasas/deficiencia , Ribonucleasas/inmunología , Imagen Individual de Molécula , Transactivadores/inmunología
3.
J Exp Med ; 216(6): 1431-1449, 2019 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-31072819

RESUMEN

Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi-dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17-induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD ) were resistant to the IL-17-mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17-mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.

4.
Nat Microbiol ; 4(9): 1532-1544, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31133753

RESUMEN

RNA-modulating factors not only regulate multiple steps of cellular RNA metabolism, but also emerge as key effectors of the immune response against invading viral pathogens including human immunodeficiency virus type-1 (HIV-1). However, the cellular RNA-binding proteins involved in the establishment and maintenance of latent HIV-1 reservoirs have not been extensively studied. Here, we screened a panel of 62 cellular RNA-binding proteins and identified NEDD4-binding protein 1 (N4BP1) as a potent interferon-inducible inhibitor of HIV-1 in primary T cells and macrophages. N4BP1 harbours a prototypical PilT N terminus-like RNase domain and inhibits HIV-1 replication by interacting with and degrading viral mRNA species. Following activation of CD4+ T cells, however, N4BP1 undergoes rapid cleavage at Arg 509 by the paracaspase named mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1). Mutational analyses and knockout studies revealed that MALT1-mediated inactivation of N4BP1 facilitates the reactivation of latent HIV-1 proviruses. Taken together, our findings demonstrate that the RNase N4BP1 is an efficient restriction factor of HIV-1 and suggest that inactivation of N4BP1 by induction of MALT1 activation might facilitate elimination of latent HIV-1 reservoirs.


Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteínas de Unión al ARN/metabolismo , Activación Viral/genética , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Línea Celular , Expresión Génica/efectos de los fármacos , Infecciones por VIH/metabolismo , Humanos , Interferón-alfa/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/virología , Ratones , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Dominios Proteicos , ARN Mensajero/metabolismo , ARN Viral/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Latencia del Virus
5.
Mucosal Immunol ; 11(4): 1203-1218, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29695841

RESUMEN

Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-κB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection.


Asunto(s)
Pulmón/inmunología , Neumonía Bacteriana/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/fisiología , Mucosa Respiratoria/metabolismo , Ribonucleasas/metabolismo , Células Th17/inmunología , Inmunidad Adaptativa , Animales , Anticuerpos Antibacterianos/metabolismo , Inmunidad Innata , Inmunoglobulina A/metabolismo , Pulmón/microbiología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Ribonucleasas/genética , Transducción de Señal
6.
J Immunol ; 199(12): 4066-4077, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29127149

RESUMEN

Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of lethality upon mutation of both Regnase-1 and Roquin. By using a Regnase-1 conditional allele, we show that mutations of both Regnase-1 and Roquin in T cells leads to massive lymphocyte activation. In contrast, mutation of either Regnase-1 or Roquin affected T cell activation to a lesser extent than the double mutation, indicating that Regnase-1 and Roquin function nonredundantly in T cells. Interestingly, Regnase-1 and Roquin double-mutant mice suffered from severe inflammation and early formation of fibrosis, especially in the heart, along with the increased expression of Ifng, but not Il4 or Il17a Consistently, mutation of both Regnase-1 and Roquin leads to a huge increase in the Th1, but not the Th2 or Th17, population in spleens compared with T cells with a single Regnase-1 or Roquin deficiency. Regnase-1 and Roquin are capable of repressing the expression of a group of mRNAs encoding factors involved in Th1 differentiation, such as Furin and Il12rb1, via their 3' untranslated regions. Moreover, Regnase-1 is capable of repressing Roquin mRNA. This cross-regulation may contribute to the synergistic control of T cell activation/polarization. Collectively, our results demonstrate that Regnase-1 and Roquin maintain T cell immune homeostasis and regulate Th1 polarization synergistically.


Asunto(s)
Miocarditis/inmunología , Miocardio/patología , Ribonucleasas/fisiología , Células TH1/inmunología , Ubiquitina-Proteína Ligasas/fisiología , Regiones no Traducidas 3' , Animales , Fibrosis , Furina/biosíntesis , Furina/genética , Regulación de la Expresión Génica/inmunología , Células HeLa , Homeostasis , Humanos , Interferón gamma/biosíntesis , Interferón gamma/genética , Interleucina-17/biosíntesis , Interleucina-17/genética , Interleucina-4/biosíntesis , Interleucina-4/genética , Células Jurkat , Activación de Linfocitos , Linfopoyesis/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Miocarditis/genética , ARN Mensajero/biosíntesis , Receptores de Interleucina-12/biosíntesis , Receptores de Interleucina-12/genética , Proteínas Recombinantes de Fusión/metabolismo , Ribonucleasas/deficiencia , Ribonucleasas/genética , Organismos Libres de Patógenos Específicos , Bazo/citología , Bazo/inmunología , Células TH1/patología , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/genética
7.
J Interferon Cytokine Res ; 37(5): 220-229, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28475459

RESUMEN

Regnase-1, also known as Zc3h12a or MCPIP1, is responsible for endonucleolytic cleavage of mRNAs encoding proteins involved in inflammatory responses. Furthermore, Regnase-1-mediated mRNA decay (RMD) is critical for the maintenance of immune homeostasis. Regnase-1 controls the magnitude of innate and adaptive immune responses, and thereby dysfunction of this protein in mice leads to the development of spontaneous systemic inflammation. During the last several years, advances have been made in understanding molecular mechanisms of RMD. In this article, unique functions of Regnase-1 in controlling inflammation are discussed.


Asunto(s)
Homeostasis/inmunología , Ribonucleasas/metabolismo , Factores de Transcripción/metabolismo , Animales , Humanos , Inflamación/metabolismo , Ratones , ARN Mensajero/metabolismo
8.
Cell Rep ; 19(8): 1614-1630, 2017 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-28538180

RESUMEN

Iron metabolism is regulated by transcriptional and post-transcriptional mechanisms. The mRNA of the iron-controlling gene, transferrin receptor 1 (TfR1), has long been believed to be negatively regulated by a yet-unidentified endonuclease. Here, we show that the endonuclease Regnase-1 is critical for the degradation of mRNAs involved in iron metabolism in vivo. First, we demonstrate that Regnase-1 promotes TfR1 mRNA decay. Next, we show that Regnase-1-/- mice suffer from severe iron deficiency anemia, although hepcidin expression is downregulated. The iron deficiency anemia is induced by a defect in duodenal iron uptake. We reveal that duodenal Regnase-1 controls the expression of PHD3, which impairs duodenal iron uptake via HIF2α suppression. Finally, we show that Regnase-1 is a HIF2α-inducible gene and thus provides a positive feedback loop for HIF2α activation via PHD3. Collectively, these results demonstrate that Regnase-1-mediated regulation of iron-related transcripts is essential for the maintenance of iron homeostasis.


Asunto(s)
Antígenos CD/metabolismo , Homeostasis , Hierro/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , Estabilidad del ARN , Receptores de Transferrina/metabolismo , Ribonucleasas/metabolismo , Anemia/metabolismo , Anemia/patología , Animales , Antígenos CD/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Duodeno/metabolismo , Ferritinas/metabolismo , Ratones , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Transferrina/genética , Elementos de Respuesta/genética , Ribonucleasas/deficiencia , Transcripción Genética
9.
Cell ; 161(5): 1058-1073, 2015 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-26000482

RESUMEN

Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.


Asunto(s)
Inflamación/metabolismo , Estabilidad del ARN , ARN Mensajero/metabolismo , Ribonucleasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Secuencia de Bases , Codón de Terminación , Células HeLa , Humanos , Inflamación/genética , Inflamación/inmunología , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Conformación de Ácido Nucleico , Polirribosomas/metabolismo , Biosíntesis de Proteínas , ARN Mensajero/química , Proteínas Ribosómicas/metabolismo , Transactivadores/metabolismo
10.
Cell ; 153(5): 1036-49, 2013 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-23706741

RESUMEN

Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3' UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4(+) T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3' UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation.


Asunto(s)
Caspasas/metabolismo , Activación de Linfocitos , Proteínas de Neoplasias/metabolismo , Ribonucleasas/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Humanos , Interleucina-2/genética , Células Jurkat , Glicoproteínas de Membrana/genética , Ratones , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas Proto-Oncogénicas c-rel/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Factores de Necrosis Tumoral/genética
11.
Biochim Biophys Acta ; 1829(6-7): 708-13, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23500036

RESUMEN

Post-transcriptional regulation is a crucial step for coordinating immune responses. Post-transcriptional mechanisms exquisitely control inflammation by increasing or decreasing both the stability of mRNAs and the efficiency of protein translation. Regulatory RNase 1 (Regnase-1, also known as Zc3h12a or MCPIP1) was identified as a novel protein harboring a CCCH-type zinc-finger domain and a PIN-like RNase domain. Regnase-1 mRNA expression is induced by Toll-like receptor (TLR) ligands, interleukin (IL)-1ß and MCP-1. Regnase-1 destabilizes mRNAs encoding immune related proteins including IL-6 and IL-12p40 via their 3' untranslated regions. In Regnase-1-deficient (-/-) macrophages, IL-6 is overproduced in response to LPS because Il6 mRNA is stabilized because of Regnase-1 deficiency. Regnase-1(-/-) mice developed severe systemic inflammation, characterized by production of autoantibodies. It is now known that Regnase-1 protein expression is dynamically regulated during the course of inflammation. Upon IL-1ß and TLR stimulation, Regnase-1 is rapidly phosphorylated by IκB kinases (IKKs) and degraded via ubiquitin-proteasome machinery. Regnase-1 degradation allows Il6 mRNA to be expressed rapidly and robustly upon stimulation. Furthermore, Regnase-1 destabilizes its own mRNA, thereby preventing excessive translation of Regnase-1 and degradation of cytokine-encoding mRNAs. In this review, we will discuss the mechanism of Regnase-1-mediated mRNA decay and describe the mechanism by which Regnase-1 is tightly regulated in innate immune cells. This article is part of a Special Issue entitled: RNA Decay mechanisms.


Asunto(s)
Macrófagos/metabolismo , Estabilidad del ARN/genética , Ribonucleasas/genética , Animales , Inmunidad Innata/genética , Interleucina-1beta/metabolismo , Ligandos , Macrófagos/inmunología , Ratones , Estructura Terciaria de Proteína , Ribonucleasas/química , Ribonucleasas/metabolismo , Receptores Toll-Like/metabolismo
12.
Nephrol Dial Transplant ; 27(12): 4378-85; discussion 4384-5, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22833619

RESUMEN

BACKGROUND: Hepcidin is associated with iron-restricted erythropoiesis. A previous cross-sectional study showed that serum hepcidin-25 levels are negatively associated with the hemoglobin concentration in non-dialysis chronic kidney disease (CKD) patients with sufficient iron stores. This longitudinal study aimed at ascertaining the association between hepcidin-25 levels and the progression of renal anemia. METHODS: We selected 335 non-dialysis CKD patients who showed hemoglobin concentrations >10 g/dL and who were not receiving erythropoiesis-stimulating agent (ESA) therapy, from among the subjects of our previous study, who had been recruited between February and June 2007 in a previous study. The primary outcome was the start of the ESA therapy or hemoglobin concentrations remaining below 10 g/dL for >3 months, by 31 December 2010. The patients were classified into high- and low-ferritin groups depending on their median ferritin levels. The Cox proportional hazard model with restricted cubic spline curve analysis was used to determine the association between hepcidin-25 levels and the outcome for each group. RESULTS: The hepcidin-25 level was a significant predictor both for the high-ferritin group (P = 0.04, linearity = 0.02) and for the low-ferritin group (P = 0.04, linearity P = 0.02). The spline curve for the high-ferritin group showed that higher hepcidin-25 levels had a high log-relative hazard. CONCLUSIONS: Higher hepcidin-25 levels predict the progression of anemia in non-dialysis CKD patients with sufficient iron stores, indicating the involvement of hepcidin in the progression of anemia in non-dialysis CKD patients.


Asunto(s)
Anemia/sangre , Anemia/etiología , Péptidos Catiónicos Antimicrobianos/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Hepcidinas , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos
13.
Cell Host Microbe ; 12(1): 109-16, 2012 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-22817992

RESUMEN

Neutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and α-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and α-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Engagement of TLR7 and TLR8 induces the generation of reactive oxygen species that trigger NET formation, leading to NET-dependent HIV-1 elimination. However, HIV-1 counteracts this response by inducing C-type lectin CD209-dependent production of interleukin (IL)-10 by dendritic cells to inhibit NET formation. IL-10 suppresses the reactive oxygen species-dependent generation of NETs induced upon TLR7 and TLR8 engagement, resulting in disrupted NET-dependent HIV-1 elimination. Therefore, NET formation is an antiviral response that is counteracted by HIV-1.


Asunto(s)
Espacio Extracelular/virología , VIH-1/patogenicidad , Interacciones Huésped-Patógeno , Neutrófilos/metabolismo , Neutrófilos/virología , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Células Dendríticas/virología , Espacio Extracelular/metabolismo , Humanos , Interleucina-10/metabolismo , Lectinas Tipo C/metabolismo , Neutrófilos/citología , Peroxidasa/metabolismo , Receptores de Superficie Celular/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , alfa-Defensinas/metabolismo
14.
J Artif Organs ; 15(1): 83-6, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21928101

RESUMEN

A 55-year-old man, who previously underwent surgical ventricular restoration and mitral valve surgery, was referred to our department for management of refractory heart and multiple organ failure. At the time of admission to our hospital, he could not be registered as a candidate for heart transplantation because of severe renal failure with a serum creatinine level of 4.6 mg/dl. We considered that he was a marginal candidate for heart transplantation; thus, it was essential to understand the etiology of renal failure and estimate whether it was reversible. Cardiac catheterization revealed poor hemodynamic function with a systemic pressure of 107/60 mmHg, cardiac index of 2.5 l/min/m(2), and pulmonary artery pressure of 63/27 mmHg, despite intense medical treatment. Contrary to biochemical examination findings of blood, renal biopsy findings showed no significant glomerular abnormality. Furthermore, the severity of tubular atrophy and interstitial fibrosis in the cortex was mild. These pathological findings suggested that the renal dysfunction in this case was possibly attributable to a hemodynamic factor. His symptoms gradually deteriorated despite an increasing dose of inotropic support; thus, we planned implantation of a Jarvik 2000 axial-flow pump (Jarvik Heart Inc., New York, NY, USA) as a bridge to eligibility, and informed consent was obtained. Because of a tight adhesion on the anterior wall, we placed the device on the lateral wall of the left ventricle, making sure not to direct the pump at the septum. Postoperatively, the implantable left ventricular assist device provided relief from heart failure symptoms as well as recovery of renal function, with serum the creatinine level at 1.2 mg/dl, which allowed the patient to become an appropriate candidate for heart transplantation. At an 18-month follow-up examination, his status was uneventful, and he is now at home awaiting heart transplantation.


Asunto(s)
Insuficiencia Cardíaca/cirugía , Ventrículos Cardíacos/cirugía , Corazón Auxiliar , Riñón/fisiopatología , Estudios de Seguimiento , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/fisiología , Humanos , Riñón/cirugía , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
15.
Nephrol Dial Transplant ; 27(3): 1076-83, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21799206

RESUMEN

BACKGROUND: Hepcidin is a central regulator of iron homeostasis. Increased hepcidin concentrations could cause iron-restricted erythropoiesis in chronic kidney disease (CKD)-associated anemia. This cross-sectional observational study was conducted to evaluate the association between hepcidin and CKD-associated anemia in non-dialysis CKD patients. METHODS: A total of 505 non-dialysis CKD patients not treated with parenteral iron were recruited, and serum hepcidin-25 levels were measured by liquid chromatography tandem mass spectrometry. Multiple linear regression analysis was used to examine the relationship between hepcidin and glomerular filtration rate (GFR) and the relationship between hemoglobin concentration and predictors including the hepcidin level. RESULTS: The median hepcidin level among the 505 CKD patients was 15.4 ng/mL (interquartile range, 5.5-33.6 ng/mL). Although hepcidin level significantly increased according to the CKD stage, multivariate analysis did not reveal an association of GFR with the hepcidin level. Hepcidin level was a significant predictor of hemoglobin concentration after the adjustment for confounders, and a significant interaction between hepcidin and ferritin was found. After stratifying at the median ferritin level, 91 ng/mL, we found a negative association between hepcidin level and hemoglobin in the high-ferritin group. A trend toward a negative association between hepcidin level and mean corpuscular volume was observed in the high-ferritin group. CONCLUSIONS: Serum hepcidin-25 levels were negatively associated with hemoglobin concentrations in non-dialysis CKD patients with sufficient iron stores. We found that ferritin modified the association between hepcidin level and hemoglobin concentration. In addition, our results confirmed that the serum hepcidin level is not associated with GFR.


Asunto(s)
Anemia/sangre , Anemia/diagnóstico , Péptidos Catiónicos Antimicrobianos/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Anciano , Anemia/etiología , Cromatografía Liquida , Comorbilidad , Estudios Transversales , Eritropoyesis , Femenino , Ferritinas/sangre , Tasa de Filtración Glomerular , Hemoglobinas/metabolismo , Hepcidinas , Humanos , Hierro/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Diálisis Renal , Espectrometría de Masas en Tándem
16.
Nat Immunol ; 12(12): 1167-75, 2011 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-22037600

RESUMEN

Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.


Asunto(s)
Citocinas/genética , Quinasa I-kappa B/metabolismo , Estabilidad del ARN , ARN Mensajero/metabolismo , Receptores de Interleucina-1/metabolismo , Ribonucleasas/metabolismo , Receptores Toll-Like/metabolismo , Secuencias de Aminoácidos , Animales , Línea Celular Tumoral , Regulación de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/genética , Ratones , Ratones Noqueados , Modelos Biológicos , Unión Proteica
17.
Clin Exp Nephrol ; 15(2): 281-4, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21161718

RESUMEN

An 80-year-old woman positive for myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was admitted with a 3-month history of fever, general malaise, and weight loss, after unsuccessful treatment with antibiotics. Upon admission, her fever persisted, and there was concomitant deterioration of renal function without active urine sediments. Furthermore, she developed hemoptysis, and chest computed tomography (CT) scan revealed bilateral diffuse alveolar hemorrhage. Although a renal biopsy was not performed because of her dementia, we initially suspected microscopic polyangiitis (MPA) on the basis of her clinical course. Because of her poor general condition, she was administered a low dose of prednisolone. Although her fever subsided, she suffered from intractable alveolar hemorrhage and eventually died from respiratory failure. During the autopsy, fibrinoid necrosis was restricted to medium-sized arteries, including the arcuate arteries of the kidneys and the bronchial arteries, without necrotizing crescentic glomerulonephritis and alveolar capillaritis. Therefore, polyarteritis nodosa (PAN) was diagnosed. It is important to distinguish between MPA and PAN because they can lead to life-threatening complications, and their treatment strategies and prognosis are different. When a patient presents with MPO-ANCA, alveolar hemorrhage, and acute renal failure with little evidence of glomerulonephritis, a differential diagnosis of PAN should be made; however, it is difficult to do so without pathological findings. Therefore, pathological examination should be carried out whenever possible.


Asunto(s)
Lesión Renal Aguda/patología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Peroxidasa/inmunología , Poliarteritis Nudosa/patología , Lesión Renal Aguda/inmunología , Femenino , Hemorragia/etiología , Humanos , Enfermedades Pulmonares/patología , Poliangitis Microscópica/diagnóstico , Poliarteritis Nudosa/diagnóstico , Alveolos Pulmonares/patología
18.
Am J Kidney Dis ; 56(2): 313-24, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20471735

RESUMEN

BACKGROUND: Multiple community-based cohort studies of mainly middle-aged and elderly populations have shown that cigarette smoking is a risk factor for chronic kidney disease. However, little information is available about an effect of cigarette smoking on progression of primary kidney diseases, including immunoglobulin A (IgA) nephropathy. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 971 of 1,001 patients with a diagnosis of IgA nephropathy in 3 major nephrology centers in Osaka, Japan, between 1992 and 2005 who enrolled in the Study of Outcome and Practice Pattern of IgA Nephropathy (STOP-IgAN). PREDICTORS: Smoking status and number of cigarettes smoked at the time of diagnosis using kidney biopsy. Dose-dependent associations between cigarette smoking and outcomes were assessed in multivariate Cox proportional hazards models. Significantly different clinical characteristics between non-/past and current smokers were controlled for using propensity score-based adjustment, stratification, and matching. OUTCOMES: 50% increase in serum creatinine level as primary outcome. A composite outcome of a 100% increase in serum creatinine level or end-stage renal disease (ESRD) and ESRD alone as secondary outcomes. RESULTS: During the median 5.8 years (interquartile range, 2.6-10.2) of the observational period, 117 participants progressed to a 50% increase in serum creatinine level and 47 advanced to ESRD. Multivariate Cox proportional hazards models identified current smokers (HR, 2.03 [95% CI, 1.33-3.10] for primary outcome) and number of cigarettes at kidney biopsy (HR, 1.21 [95% CI, 1.06-1.39] per 10 cigarettes per day) as significant predictors of outcomes. Propensity score-based models confirmed these results. Tests for interaction showed that the association of current smoking with adverse outcomes was stronger in those with lower compared with higher estimated glomerular filtration rates. LIMITATION: Baseline smoking status was not verified using biochemical tests. Smoking status during the observational period was unavailable. CONCLUSIONS: Cigarette smoking, in a dose-dependent manner, was identified as a key prognostic factor in IgA nephropathy. Smoking cessation should be encouraged as part of the treatment for IgA nephropathy.


Asunto(s)
Glomerulonefritis por IGA/epidemiología , Glomerulonefritis por IGA/patología , Fumar/epidemiología , Adulto , Creatinina/sangre , Progresión de la Enfermedad , Modificador del Efecto Epidemiológico , Femenino , Glomerulonefritis por IGA/sangre , Humanos , Fallo Renal Crónico/sangre , Modelos Logísticos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Fumar/efectos adversos , Adulto Joven
19.
Nihon Jinzo Gakkai Shi ; 51(5): 550-6, 2009.
Artículo en Japonés | MEDLINE | ID: mdl-19715163

RESUMEN

A 80-year-old man was admitted to our hospital because of coughing, hemosputum and dyspnea. As a chest X-ray showed infiltrates of the right lung, he was diagnosed as bacterial pneumonia and treated with antibiotics. However, after a few days, he exhibited hemoptysis and developed severe dyspnea, while laboratory findings showed rapid elevation of the serum creatinine level (5.55 mg dL). Computed tomography (CT) revealed large areas of ground glass opacity in the right lung, hence the hemoptysis was considered to be due to alveolar hemorrhage. As he had been diagnosed as chronic renal failure a few years before this admission and we also noticed that interstitial pneumonia with a slightly elevated level of C-reactive protein had existed from that time, ANCA-associated vasculitis was suspected to be the underlying pathogenesis. Accordingly, he was started on methylprednisolone pulse therapy and temporary hemodialysis resulted in improvement of dyspnea and renal function. PR3-ANCA was 12.4 EU, so he was diagnosed as PR3-ANCA-associated vasculitis. After a few days, he suddenly complained of abdominal pain, developing hypotension and anemia. Abdominal CT showed an irregular low-density mass in the right muscle, so he was diagnosed as rectus muscle hematoma. Surgery was performed and a massive hematoma was found in the rectus muscle without any ruptures of macroscopic vessels in the abdomen. Bleeding could not be stopped followed by multiple organ failure and the patient died four days postoperatively. Rectus muscle hematoma is an uncommon cause of acute abdomen, and has been reported in about 100 cases in Japan. It occurs because of a tear in epigastric vessels and is usually managed conservatively with a good prognosis, although hemodynamically unstable cases require surgery. To the best of the authors' knowledge, this is the first case of rectus muscle hematoma complicated with ANCA-associated vasculitis.


Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/sangre , Hematoma/etiología , Enfermedades Musculares/etiología , Recto del Abdomen , Vasculitis/complicaciones , Vasculitis/diagnóstico , Anciano de 80 o más Años , Autopsia , Resultado Fatal , Hematoma/diagnóstico , Hematoma/cirugía , Humanos , Masculino , Insuficiencia Multiorgánica/etiología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/cirugía
20.
Nephrol Dial Transplant ; 24(12): 3686-94, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19420105

RESUMEN

BACKGROUND: Renal prognosis of IgA nephropathy (IgAN) is affected by environmental and genetic factors. Other studies demonstrated that some atherosclerotic disease-related genes were significantly associated with renal prognosis. METHODS: The Polymorphism REsearch to DIstinguish genetic factors Contributing To progression of IgAN (PREDICT-IgAN) was a multicentre retrospective observational study to investigate associations between progression of IgAN (a 50% increase of serum creatinine level and slope of eGFR) and a hundred atherosclerotic disease-related gene polymorphisms, mainly single nucleotide polymorphisms (SNPs) in 320 IgAN patients who had more than a normal range of urinary protein (> or =0.25 g/day) at diagnosis. RESULTS: During 8.3 +/- 4.2 years of a follow-up period, 83 patients (25.9%) developed progression. In log-rank tests, glycoprotein Ia GPIa C807T and G873A and intercellular adhesion molecule-1 ICAM-1 A1548G (K469E) were found to be significantly associated with progression even after adjustment for multiple comparisons by the method of Bonferroni (adjusted P = 0.0174, 0.0176 and 0.0430, respectively). In a multivariate Cox proportional-hazards model, GPIa 807TT (873CC) [versus 807TT, adjusted hazard ratio 2.05 (95% confidence interval 1.13-3.71)] and ICAM-1 1548GG [versus 1548AA, 2.55 (1.40-4.65)] were identified as independent genetic predictors of progression, along with conventional clinical prognostic factors such as eGFR, urinary protein and use of antihypertensives at diagnosis. CONCLUSIONS: PREDICT-IgAN distinguished GPIa C807T/ G873A and ICAM-1 A1548G from multiple athero- sclerotic disease-related gene polymorphisms by their predictive indicator for progression of IgAN.


Asunto(s)
Glomerulonefritis por IGA/genética , Polimorfismo Genético , Adulto , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos
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