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Neuropatías Amiloides Familiares/genética , Hipotensión Ortostática/genética , Prealbúmina/genética , Retención Urinaria/genética , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/patología , Femenino , Humanos , Hipotensión Ortostática/complicaciones , Hipotensión Ortostática/patología , Masculino , Persona de Mediana Edad , Mutación , Linaje , Retención Urinaria/patologíaRESUMEN
PURPOSE: Late genitourinary (GU) toxicity after radiation therapy limits the quality of life of prostate cancer survivors; however, efforts to explain GU toxicity using patient and dose information have remained unsuccessful. We identified patients with a greater congenital GU toxicity risk by identifying and integrating patterns in genome-wide single nucleotide polymorphisms (SNPs). METHODS AND MATERIALS: We applied a preconditioned random forest regression method for predicting risk from the genome-wide data to combine the effects of multiple SNPs and overcome the statistical power limitations of single-SNP analysis. We studied a cohort of 324 prostate cancer patients who were self-assessed for 4 urinary symptoms at 2 years after radiation therapy using the International Prostate Symptom Score. RESULTS: The predictive accuracy of the method varied across the symptoms. Only for the weak stream endpoint did it achieve a significant area under the curve of 0.70 (95% confidence interval 0.54-0.86; P = .01) on hold-out validation data that outperformed competing methods. Gene ontology analysis highlighted key biological processes, such as neurogenesis and ion transport, from the genes known to be important for urinary tract functions. CONCLUSIONS: We applied machine learning methods and bioinformatics tools to genome-wide data to predict and explain GU toxicity. Our approach enabled the design of a more powerful predictive model and the determination of plausible biomarkers and biological processes associated with GU toxicity.
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Estudio de Asociación del Genoma Completo/métodos , Aprendizaje Automático , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/radioterapia , Trastornos Urinarios/genética , Sistema Urogenital/efectos de la radiación , Antagonistas de Andrógenos/uso terapéutico , Área Bajo la Curva , Braquiterapia/efectos adversos , Intervalos de Confianza , Técnicas de Genotipaje , Humanos , Síntomas del Sistema Urinario Inferior , Masculino , Nocturia/genética , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/tratamiento farmacológico , Calidad de Vida , Análisis de Regresión , Reproducibilidad de los Resultados , Riesgo , Evaluación de Síntomas , Retención Urinaria/genética , Micción/genética , Trastornos Urinarios/diagnósticoRESUMEN
AIMS: MicroRNAs (miRs) control post-transcriptional gene expression, and this is relevant in understanding better chronic diseases and treatment outcomes. The role of miRs in the pathology and treatment outcomes of overactive bladder (OAB) is unknown. In this study, we assessed the differential expression of miRs in OAB patients responding with either normal or elevated post-void residual volumes (PVRs) ≥200 mL following intradetrusor injection of onabotulinumtoxin-A (onaBoNT-A). METHODS: Female OAB patients refractory to OAB drugs were consented for this study. Cystoscopic-guided punch bladder biopsy was obtained at the time of injection of onaBoNT-A 100 units. The expression of 13 miR species, selected for their known effect on neurotrophin expression and smooth muscle function, was measured. PVRs and urine nerve growth factor (NGF) levels were measured at baseline and at the follow-up visit. RESULTS: Fourteen patients with mean age of 66 years were consented. Of these patients, nine maintained PVRs <200 mL after onaBoNT-A injection to comprise the low PVR group. The other five patients with PVRs ≥200 mL comprised the high PVR group. The expression of miR221 and miR125b was upregulated by 11- and 2-fold, respectively, in patients who responded with low PVRs after onaBoNT-A (P < 0.05). Urine NGF levels at baseline were not different between the two groups. CONCLUSIONS: This study suggests that deficiency in the pretreatment expression of miR221 and miR125b may predispose OAB patients to high PVRs following intradetrusor onaBoNT-A. Additional studies are needed to better understand the role of miRs in OAB.
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Toxinas Botulínicas Tipo A/administración & dosificación , MicroARNs/biosíntesis , Fármacos Neuromusculares/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/metabolismo , Retención Urinaria/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Biomarcadores/metabolismo , Biopsia con Aguja , Toxinas Botulínicas Tipo A/uso terapéutico , Femenino , Humanos , Inyecciones Intramusculares , Masculino , MicroARNs/genética , Persona de Mediana Edad , Factor de Crecimiento Nervioso/orina , Fármacos Neuromusculares/uso terapéutico , Valor Predictivo de las Pruebas , Regulación hacia Arriba , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria Hiperactiva/genética , Vejiga Urinaria Hiperactiva/patología , Retención Urinaria/inducido químicamente , Retención Urinaria/genética , Retención Urinaria/orinaRESUMEN
Microglia and other tissue-resident macrophages within the central nervous system (CNS) have essential roles in neural development, inflammation and homeostasis. However, the molecular pathways underlying their development and function remain poorly understood. Here we report that mice deficient in NRROS, a myeloid-expressed transmembrane protein in the endoplasmic reticulum, develop spontaneous neurological disorders. NRROS-deficient (Nrros-/-) mice show defects in motor functions and die before 6 months of age. Nrros-/- mice display astrogliosis and lack normal CD11bhiCD45lo microglia, but they show no detectable demyelination or neuronal loss. Instead, perivascular macrophage-like myeloid cells populate the Nrros-/- CNS. Cx3cr1-driven deletion of Nrros shows its crucial role in microglial establishment during early embryonic stages. NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function. Our study reveals a NRROS-mediated pathway that controls CNS-resident macrophage development and affects neurological function.
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Astrocitos/metabolismo , Sistema Nervioso Central/embriología , Regulación del Desarrollo de la Expresión Génica , Microglía/metabolismo , Células Mieloides/metabolismo , Enfermedades del Sistema Nervioso/genética , Proteínas/genética , Animales , Astrocitos/citología , Western Blotting , Sistema Nervioso Central/citología , Citometría de Flujo , Inmunohistoquímica , Cojera Animal/genética , Proteínas de Unión a TGF-beta Latente , Locomoción , Macrófagos/citología , Macrófagos/metabolismo , Proteínas de la Membrana , Ratones , Ratones Noqueados , Microglía/citología , Células Mieloides/citología , Postura , Factores de Transcripción/genética , Incontinencia Urinaria/genética , Retención Urinaria/genéticaRESUMEN
Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.
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Proteína 2 de Unión a Metil-CpG/genética , Mutación , Insuficiencia Renal/genética , Síndrome de Rett/genética , Obstrucción Uretral/genética , Retención Urinaria/genética , Animales , Bases de Datos Factuales , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/deficiencia , Ratones , Penetrancia , Insuficiencia Renal/complicaciones , Insuficiencia Renal/mortalidad , Insuficiencia Renal/fisiopatología , Síndrome de Rett/complicaciones , Síndrome de Rett/mortalidad , Síndrome de Rett/fisiopatología , Especificidad de la Especie , Análisis de Supervivencia , Obstrucción Uretral/complicaciones , Obstrucción Uretral/mortalidad , Obstrucción Uretral/fisiopatología , Retención Urinaria/complicaciones , Retención Urinaria/mortalidad , Retención Urinaria/fisiopatologíaRESUMEN
Here we show that male, but not female mice lacking expression of the GTPase M-Ras developed urinary retention with distention of the bladder that exacerbated with age but occurred in the absence of obvious anatomical outlet obstruction. There were changes in detrusor morphology in Mras-/- males: Smooth muscle tissue, which exhibited a compact organization in WT mice, appeared disorganized and became increasingly 'layered' with age in Mras-/- males, but was not fibrotic. Bladder tissue near the apex of bladders of Mras-/- males exhibited hypercontractility in response to the cholinergic agonist carbachol in in vitro, while responses in Mras-/- females were normal. In addition, spontaneous phasic contractions of detrusors from Mras-/- males were increased, and Mras-/- males exhibited urinary incontinence. We found that expression of the muscarinic M2 and M3 receptors that mediate the cholinergic contractile stimuli of the detrusor muscle was dysregulated in both Mras-/- males and females, although only males exhibited a urinary phenotype. Elevated expression of M2R in young males lacking M-Ras and failure to upregulate M3R with age resulted in significantly lower ratios of M3R/M2R expression that correlated with the bladder abnormalities. Our data suggests that M-Ras and M3R are functionally linked and that M-Ras is an important regulator of male bladder control in mice. Our observations also support the notion that bladder control is sexually dimorphic and is regulated through mechanisms that are largely independent of acetylcholine signaling in female mice.
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Proteínas de Unión al GTP Monoméricas/deficiencia , Receptor Muscarínico M2/fisiología , Receptor Muscarínico M3/fisiología , Caracteres Sexuales , Vejiga Urinaria/metabolismo , Incontinencia Urinaria/fisiopatología , Retención Urinaria/fisiopatología , Acetilcolina/fisiología , Envejecimiento/genética , Envejecimiento/fisiología , Animales , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/fisiología , Contracción Muscular , Músculo Liso/metabolismo , Fenotipo , Proteinuria/genética , Proteinuria/fisiopatología , ARN Mensajero/biosíntesis , Receptor Muscarínico M2/biosíntesis , Receptor Muscarínico M2/genética , Receptor Muscarínico M3/biosíntesis , Receptor Muscarínico M3/genética , Vejiga Urinaria/patología , Vejiga Urinaria Hiperactiva/genética , Vejiga Urinaria Hiperactiva/fisiopatología , Incontinencia Urinaria/genética , Retención Urinaria/genética , Micción/fisiología , Proteínas rasRESUMEN
INTRODUCTION: To study the pathophysiology of dysfunctional voiding, we have previously developed a model of stress-induced voiding dysfunction. We have shown that cyclosporine A (CsA), an inhibitor of the Ca(2+)-calmodulin complex, can prevent social stress-induced urinary retention. However, treatment with cyclosporine has not had an effect on the increase in the stress peptide corticotrophin-releasing factor (CRF) in Barrington's nucleus, which is involved in the micturition pathway. OBJECTIVE: We now investigate whether cyclosporine administered after stress can reverse the abnormal voiding phenotype, and whether it has effects on the bladder wall itself, or on the stress response within Barrington's nucleus. MATERIALS AND METHODS: Six-week old Swiss-Webster mice were exposed to aggressor males for 1 h a day, followed by 23 h of barrier separation. In a long-term trial, 1 month of stress was followed by single-cage housing for 6 months. In a separate CsA reversal trial, mice either received CsA in drinking water or had plain drinking water during 1 month of single-cage housing during recovery. Bladder contractile function was examined on a Guth myograph. Nuclear translocation of myocyte enhancing factor (MEF)-2 and NFAT (nuclear factor of activated T cells) in the bladder was assessed using electrophoretic mobility shift assays (EMSAs). The expression of CRF was determined in Barrington's nucleus using in situ hybridization. RESULTS: Voiding dysfunction persisted for up to 6 months after stress exposure while mice recovered in single-cage housing. In the CsA reversal trial, voiding patterns improved when they received CsA in water during single-cage housing following stress, whereas those that underwent single-cage housing alone had persistent abnormal voiding (Fig. A). There was no difference between CRF levels in Barrington's nucleus between reversal groups (p = 0.42) (Fig. B), possibly indicating a direct effect on the bladder rather than a persistent stress effect. There were no differences in the contractility of bladder wall muscle. CsA decreased the nuclear translocation of MEF-2 and NFAT induced by stress (Fig. C,D). CONCLUSION: CsA reverses stress-induced urinary retention, but does not change the stress-induced CRF increase in Barrington's nucleus. Furthermore, bladder smooth muscle contractility is unchanged by CsA; however, there are changes in the levels of the downstream transcription factors MEF-2 and NFAT. We suspect that additional CsA responsive neural changes play a pivotal role in the abnormal voiding phenotype following social stress.
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Hormona Liberadora de Corticotropina/genética , Regulación de la Expresión Génica , ARN Mensajero/genética , Estrés Psicológico , Vejiga Urinaria/fisiopatología , Retención Urinaria/fisiopatología , Micción/fisiología , Animales , Hormona Liberadora de Corticotropina/biosíntesis , Estudios de Seguimiento , Hibridación in Situ , Masculino , Ratones , Recuperación de la Función , Factores de Tiempo , Retención Urinaria/genética , Retención Urinaria/metabolismoRESUMEN
Polydypsia and polyuria are frequent symptoms in patients with sellar masses caused by neurohypophyseal diabetes insipidus. Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the arginine vasopressin (AVP) -neurophysin II (NPII) gene, should be considered as a rare differential diagnosis. A delayed diagnosis bears the risk of life-threatening electrolyte imbalances and permanent urinary tract damage, leading to impaired quality of life.We present a Caucasian kindred of at least 4 generations with FNDI.Clinical histories, endocrine para-meters, and results of molecular analyses of the AVP gene are presented with a review of the literature on diabetes insipidus (DI) related urinary tract dilatation.Polyuria and polydipsia were only reported based on explicit and thorough interrogation after more than 4 years of clinical follow-up. A novel heterozygous mutation in the AVP gene was found in all examined symptomatic subjects (c.1-33_c.4del37nt). A literature review revealed that non-obstructive hydronephrosis (NOH) is a rare but known complication of DI.Since increased fluid intake is often a typical familial pattern in adFNDI, it is frequently missed as being pathologic in affected patients, therefore a detailed clinical history of drinking volumes is of critical importance. AVP gene testing is an important component in the confirmation of the diagnosis. Otherwise unexplainable NOH should lead to further investigations and evaluation of rare diseases like FNDI.
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Arginina Vasopresina/genética , Análisis Mutacional de ADN , Diabetes Insípida/diagnóstico , Diabetes Insípida/genética , Pelvis Renal/anomalías , Neurofisinas/genética , Uréter/anomalías , Vejiga Urinaria/anomalías , Niño , Diagnóstico Tardío , Dilatación Patológica/diagnóstico , Dilatación Patológica/genética , Estudios de Seguimiento , Humanos , Hidronefrosis/diagnóstico , Hidronefrosis/genética , Pruebas de Función Renal , Imagen por Resonancia Magnética , Masculino , Linaje , Precursores de Proteínas , Análisis de Secuencia de ADN , Retención Urinaria/diagnóstico , Retención Urinaria/genética , VasopresinasRESUMEN
Heat shock protein 27 (Hsp27) can regulate actin cytoskeleton dynamics and contractile protein activation. This study investigates whether Hsp27 expression is related to bladder contractile dysfunction after acute urinary retention (AUR). Female rats were randomized either to AUR by urethral ligation or to normal control group. Bladder and smooth muscle strip contraction at time points from 0 h to 7 days after AUR were estimated by cystometric and organ bath studies. Hsp27 expression in bladder tissue at each time point was detected with immunofluorescence, Western blots, and real-time PCR. Expression of the three phosphorylated forms of Hsp27 was detected by Western blots. Smooth muscle ultrastructure was observed by transmission electron microscopy. Data suggest that maximum detrusor pressure and both carbachol-induced and spontaneous detrusor strip contraction amplitude decreased gradually for the duration from 0 to 6 h, and then increased gradually to near-normal values at 24 h. Treatment of muscle strips with the p38MAK inhibitor, SB203580, inhibited carbachol-induced contractions. Smooth muscle ultrastructure damage was the highest at 6 h after AUR, and then lessened gradually during next 7 days, and ultrastructure was close to normal. Expressions of Hsp27 mRNA and protein and the proteins of the three phosphorylated forms were higher at 0 h, decreased to lower levels up to 6 h, and then gradually increased. Therefore, we conclude that rat bladder contractile function after AUR worsens during 0-6 h, and then gradually recovers. The findings of the current study suggest that Hsp27 modulates bladder smooth muscle contraction after AUR, and that phosphorylation of Hsp27 may be an important pathway modulating actin cytoskeleton dynamics in bladder smooth muscle contraction and reconstruction after injury.
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Proteínas de Choque Térmico HSP27/metabolismo , Contracción Muscular/fisiología , Músculo Liso/fisiopatología , Vejiga Urinaria/fisiopatología , Retención Urinaria/metabolismo , Retención Urinaria/fisiopatología , Animales , Western Blotting , Carbacol/farmacología , Femenino , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico HSP27/genética , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Músculo Liso/ultraestructura , Fosforilación/efectos de los fármacos , Presión , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/ultraestructura , Retención Urinaria/genética , Retención Urinaria/patologíaRESUMEN
Acute bladder distension causes various morphologic and functional changes, in part through altered gene expression. We aimed to investigate the physiologic role of PTHrP, which is up-regulated in an acute bladder distension model in female rats. In the control Empty group, bladders were kept empty for 6 hours, and in the Distension group, bladders were kept distended for 3 hours after an artificial storing-voiding cycle for 3 hours. In the Distention group bladder, up-regulation of transcripts was noted for 3 genes reported to be up-regulated by stretch in the cultured bladder smooth muscle cells in vitro. Further transcriptome analysis by microarray identified PTHrP as the 22nd highest gene up-regulated in Distension group bladder, among more than 27,000 genes. Localization of PTHrP and its functional receptor, PTH/PTHrP receptor 1 (PTH1R), were analyzed in the untreated rat bladders and cultured bladder cells using real-time RT-PCR and immunoblotting, which revealed that PTH1R and PTHrP were more predominantly expressed in smooth muscle than in urothelium. Exogenous PTHrP peptide (1-34) increased intracellular cAMP level in cultured bladder smooth muscle cells. In organ bath study using bladder strips, the PTHrP peptide caused a marked reduction in the amplitude of spontaneous contraction but caused only modest suppression for carbachol-induced contraction. In in vivo functional study by cystometrogram, the PTHrP peptide decreased voiding pressure and increased bladder compliance. Thus, PTHrP is a potent endogenous relaxant of bladder contraction, and autocrine or paracrine mechanism of the PTHrP-PTH1R axis is a physiologically relevant pathway functioning in the bladder.
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Contracción Muscular/fisiología , Músculo Liso/fisiopatología , Proteína Relacionada con la Hormona Paratiroidea/fisiología , Vejiga Urinaria/fisiopatología , Animales , Carbacol/farmacología , Células Cultivadas , Agonistas Colinérgicos/farmacología , AMP Cíclico/metabolismo , Femenino , Perfilación de la Expresión Génica , Immunoblotting , Técnicas In Vitro , Contracción Muscular/genética , Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteína Relacionada con la Hormona Paratiroidea/genética , Proteína Relacionada con la Hormona Paratiroidea/metabolismo , Fragmentos de Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Hormona Paratiroídea Tipo 1/genética , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vejiga Urinaria/metabolismo , Retención Urinaria/genética , Retención Urinaria/metabolismo , Retención Urinaria/fisiopatologíaRESUMEN
We previously showed that complete loss of smooth muscle myosin heavy chain isoform 2 (SM2) resulted in postnatal lethality, but in het mice a partial loss of SM2 (SM2(+/-)) was accompanied by down-regulation of SM1 with unaltered SM2:SM1 ratio. To determine whether a normal bladder function would be maintained throughout its lifespan, we aged WT and SM2(+/-) mice up to 18 months and analyzed a) SM2:SM1 ratio b) bladder smooth muscle structure and c) function in SM2(+/-) het mice. A notable finding was that ~50% of 15-18 months old male SM2(+/-) mice exhibited urinary retention in bladder with the distention of upper urethra. In SM2(+/-) mouse bladder with urinary retention, the SM2:SM1 ratio was decreased but not in SM2(+/-) mouse bladder that did not develop urinary retention. Interestingly in the distended bladder the expression levels of α-actin and tropomyosin remained unaltered despite a reduction in the number of myosin thick filaments. These distended bladders showed hypersensitivity to submaximal K(+) depolarization and M3-receptor stimulation, without a significant increase in myosin light chain phosphorylation. We therefore suggest that a partial loss of SM2 may predispose male mice to develop lower urinary tract obstruction during ageing. In addition our data suggest that bladder obstruction can cause a further reduction in SM2 expression and SM2:SM1 ratio, and a hyper-contractility of the bladder smooth muscle.
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Contracción Muscular , Músculo Liso/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Obstrucción Ureteral/metabolismo , Actinas/biosíntesis , Actinas/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Regulación de la Expresión Génica/genética , Masculino , Ratones , Músculo Liso/patología , Cadenas Pesadas de Miosina/genética , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Fosforilación/genética , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Tropomiosina/biosíntesis , Tropomiosina/genética , Obstrucción Ureteral/genética , Obstrucción Ureteral/patología , Retención Urinaria/genética , Retención Urinaria/metabolismo , Retención Urinaria/patologíaRESUMEN
It has been demonstrated that increases in poly(ADP-ribose) polymerase (PARP) activity causes damage to several organs under ischemia/reperfusion (I/R) conditions. The aims of this study were to investigate whether inhibition of PARP could suppress apoptosis in the bladder following acute urinary retention (AUR) and subsequent bladder emptying. Twelve-week-old male Sprague Dawley rats were divided into a control group, saline treated group, and 3-aminobenzamide (3-AB, a specific PARP inhibitor)-treated group. Sixty minutes after the administration of saline and 3-AB, the saline and 3-AB-treated groups had 60 min of over-distension and followed by 2 h of drainage. The degree of bladder apoptosis, levels of malondialdehyde (MDA), ATP and nicotinamide adenine dinucleotide (NAD+); expression of poly(ADP-ribose) (PAR), phosphorylation of protein kinase B (Akt); and levels of Bcl-2, Bax, and caspase 3 activity in the bladder were determined. Molecular and histological analyses showed that bladder apoptosis was associated with increases in the amount of PAR and decreases in ATP and NAD+ levels in the saline treated group. In addition, phosphorylated Akt and Bcl-2/Bax ratio were significantly decreased. The activity of caspase 3 was significantly increased in the saline treated group. Inhibition of PARP significantly increased the levels of ATP and NAD+, phosphorylation of Akt, and Bcl-2/Bax ratio, and significantly reduced the activation of caspase 3. As a result, apoptosis in the bladder was attenuated. These results indicate that PARP activation may be involved in apoptosis in the bladder induced by AUR and subsequent emptying via energy depletion and suppression of Akt activity.
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Regulación hacia Abajo , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Vejiga Urinaria/metabolismo , Animales , Apoptosis , Humanos , Masculino , Poli Adenosina Difosfato Ribosa/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/citología , Vejiga Urinaria/lesiones , Retención Urinaria/enzimología , Retención Urinaria/genética , Retención Urinaria/metabolismo , Retención Urinaria/fisiopatologíaAsunto(s)
Colágeno Tipo IV/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Retención Urinaria/etiología , Retención Urinaria/genética , Enfermedad Aguda , Sustitución de Aminoácidos/genética , Infarto Encefálico/etiología , Infarto Encefálico/genética , Infarto Encefálico/metabolismo , Hemorragia Cerebral/etiología , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Humanos , Leucoencefalopatías/etiología , Leucoencefalopatías/genética , Leucoencefalopatías/metabolismo , Masculino , Retención Urinaria/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To observe the effect of electroacupuncture (EA) of different acupoints on the expression of brain-derived neurotrophic factor (BDNF) and tropomyosine receptor kinase B (TrkB) in the spinal cord and the excitability of detrusor muscle of the uninary bladder in rats with urinary retention owing to spinal cord injury (SCI). METHODS: A total of 100 female SD rats were randomly divided into normal, sham-operation (sham), model, EA-Guanyuan (CV 4), and EA-Shuidao (ST 28) groups, with 20 cases in each. SCI induced urinary retention model was established by using weight dropping method. EA (1 mA, 2 Hz/15 Hz) was applied to "Guanyuan" (CV 4) and "Shuidao" (ST 28) respectively for 20 min, once a day for 10 days. The excitability (tone, contraction frequency) of the detrusor muscle of the bladder was detected in vitro by using electrophysiological method, and the expression of BDNF and TrkB in spinal cord was determined by immunohistochemistry staining. RESULTS: In comparison with normal control and sham groups, the tension and the contraction frequency of detrusor muscle in model group lowered significantly (P<0.05), while compared with model group, both the tension and contraction frequency of detrusor muscle increased pronouncedly in EA-CV 4 and EA-ST 28 groups (P<0.05), and the effect of EA-CV 4 was apparently superior to that of EA-ST 28 (P<0.05). In comparison with normal and sham groups, the BDNF and TrkB immunoreaction positive cells in the spinal cord were significantly more in model group (P<0.05). Compared with model group, those of EA-CV 4 and EA-ST 28 groups were obviously further increased (P<0.05), and the effect of EA-CV 4 group was markedly superior to that of EA-ST 28 group (P<0.05). CONCLUSION: EA of CV 4 and ST 28 can raise the excitability of the smooth muscle of the uninary bladder in rats with SCI-induced urinary retention, which may be related to its effects in upregulating the expression of BDNF and TrkB in the spinal cord. The effects of EA of CV 4 were evidently superior to those of EA of ST 28.
Asunto(s)
Puntos de Acupuntura , Factor Neurotrófico Derivado del Encéfalo/genética , Electroacupuntura , Músculo Liso/metabolismo , Receptor trkB/genética , Traumatismos de la Médula Espinal/complicaciones , Retención Urinaria/terapia , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptor trkB/metabolismo , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/terapia , Vejiga Urinaria/metabolismo , Vejiga Urinaria/fisiopatología , Retención Urinaria/etiología , Retención Urinaria/genética , Retención Urinaria/metabolismoRESUMEN
UNLABELLED: Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenal-intact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodium- and potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium- and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum- and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium- and potassium-dependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. CONCLUSION: Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium- and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium- and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids.
Asunto(s)
Colestasis/sangre , Receptores de Mineralocorticoides/fisiología , Sodio/metabolismo , Retención Urinaria/metabolismo , Adrenalectomía , Animales , Colestasis/genética , Modelos Animales de Enfermedad , Homeostasis , Masculino , Ratones , Ratones Endogámicos , Nefronas/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Retención Urinaria/genéticaRESUMEN
Idiopathic detrusor underactivity (DU) and detrusor decompensation which develops following partial bladder outlet obstruction (pBOO) are both associated with smooth muscle degeneration and fibrosis. Macrophage migration inhibitory factor (MIF), an important mediator of bladder inflammation, has been shown to promote fibroblast survival and muscle death in other tissues. We evaluated the hypothesis that MIF has similar actions in the bladder by studying detrusor responses to pBOO or sham surgery in anesthetized female mice rendered null for the mif gene (MIF KO) and in wild-type (WT) controls, all killed 3 wk after surgery. WT mice revealed intense MIF immunoreactivity in urothelial cells which decreased, without change in overall mif mRNA levels. Stereologically sound quantitative morphometric measurements were performed in the middetrusor region of each bladder. MIF KO bladders were normal in appearance, yet were 30-40% heavier, with increased middetrusor collagen and muscle, compared with WT controls. In WT mice, pBOO increased the collagen-to-muscle ratio 1.9-fold and middetrusor collagen 1.8-fold, while nucleated muscle counts were 22% lower. In MIF KO mice, by contrast, pBOO had no significant effect on any of these parameters. In primary bladder muscle cultures, treatment with rMIF protein increased TUNEL staining, raising the proportion of early and late apoptotic cells on flow cytometry. Our studies implicate MIF in the sequence of events leading to detrusor muscle loss and fibrosis in obstruction. They raise the possibility that strategies designed to antagonize MIF synthesis, release, or biological activity could prevent or delay DU and urinary retention.
Asunto(s)
Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Músculo Liso/patología , Obstrucción del Cuello de la Vejiga Urinaria/patología , Animales , Apoptosis , Peso Corporal , Células Cultivadas , Colágeno/metabolismo , Fibrosis , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso/metabolismo , Músculo Liso/fisiopatología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Tamaño de los Órganos , Obstrucción del Cuello de la Vejiga Urinaria/genética , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Retención Urinaria/genética , Retención Urinaria/patología , Retención Urinaria/fisiopatologíaRESUMEN
The syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystemic disorder associated in most of the patients with an A to G transition at nucleotide position 3243 in the transfer RNA (tRNA)Leu(UUR) (A3243G) of the mitochondrial DNA. This syndrome is characterized by the preponderant involvement of skeletal muscle and central nervous system, but urinary or gastrointestinal symptoms are seldom documented. Here we report an unusual case of a 52-year-old woman with a clinical phenotype characterized by encephalopathy, left hemiparesis, urinary retention and gastrointestinal pseudo-obstruction. She had the classical A3243G mitochondrial DNA point mutation of MELAS syndrome. We also present a clinically heterogeneous multigenerational pedigree with several affected members in the maternal lineage.
Asunto(s)
ADN Mitocondrial/genética , Seudoobstrucción Intestinal/genética , Síndrome MELAS/genética , Retención Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Linaje , Mutación Puntual/genéticaRESUMEN
PURPOSE: The EL mouse is an animal model for multifactorial idiopathic epilepsy. Although EL mice have been studied extensively for >45 years, the etiology of male sudden death and its relation to seizures have not been defined. Here we investigated the cause of EL male sudden death and its relation to epilepsy. METHODS: For histopathologic analysis, the terminally ill EL mice (n = 15) were killed, and the tissues were fixed. Blood chemical composition was compared between the terminally ill EL (n = 9) and the healthy age-matched EL (n = 17) and DDY (n = 11) males. To determine the effect of the ketogenic diet (KD) on sudden male death, young male EL mice (P30) were randomly separated into two groups that were fed ad libitum with either Agway lab chow (control n = 38) or with the KD (treated, n = 39) for 5 months. The genetic predisposition to sudden death was analyzed in the backcross generation (n = 106) of a cross between EL and the nonepileptic ABP strains. RESULTS: Sudden death coincided with the onset of seizures (70-80 days) and affected 94% of male EL mice by age 300 days. Urethral plugs were observed histologically in 13 of 15 longitudinally sectioned penises. Concentrations of blood urea nitrogen, creatinine, phosphorus, and calcium in the terminally ill mice were significantly elevated when compared with those of healthy animals. None of the mice treated with the KD experienced sudden death, whereas 15 (39%) of the untreated control mice died by age 5 months. The sudden death in male EL mice was inherited as an autosomal recessive sex-limited lethal trait. CONCLUSIONS: The cause of sudden death in male EL mice arises from abnormal ejaculation, which produces a urethral plug with consequent urinary retention and acute severe uremia. The coincident onset of seizures and sudden death in EL males suggests that a sexual dysfunction is associated with epilepsy in this model.