RESUMEN
Heart failure is frequently accompanied by kidney failure and co-incidence of these organ failures worsens the mortality in patients with heart failure. Recent clinical observations revealed that increased kidney venous pressure, rather than decreased cardiac output, causes the deterioration of kidney function in patients with heart failure. However, the underlying pathophysiology is unknown. Here, we found that decreased blood flow velocity in peritubular capillaries by kidney congestion and upregulation of endothelial nuclear factor-κB (NF-κB) signaling synergistically exacerbate kidney injury. We generated a novel mouse model with unilateral kidney congestion by constriction of the inferior vena cava between kidney veins. Intravital imaging highlighted the notable dilatation of peritubular capillaries and decreased kidney blood flow velocity in the congestive kidney. Damage after ischemia reperfusion injury was exacerbated in the congestive kidney and accumulation of polymorphonuclear leukocytes within peritubular capillaries was noted at the acute phase after injury. Similar results were obtained in vitro, in which polymorphonuclear leukocytes adhesion on activated endothelial cells was decreased in flow velocity-dependent manner but cancelled by inhibition of NF-κB signaling. Pharmacological inhibition of NF-κB for the mice subjected by both kidney congestion and ischemia reperfusion injury ameliorated the accumulation of polymorphonuclear leukocytes and subsequent exacerbation of kidney injury. Thus, our study demonstrates the importance of decreased blood flow velocity accompanying activated NF-κB signaling in aggravation of kidney injury. Hence, inhibition of NF-κB signaling may be a therapeutic candidate for the vicious cycle between heart and kidney failure with increased kidney venous pressure.
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Lesión Renal Aguda , Daño por Reperfusión , Lesión Renal Aguda/terapia , Animales , Células Endoteliales , Humanos , Riñón , Ratones , FN-kappa B , Daño por Reperfusión/complicacionesRESUMEN
Tubular atrophy is a common pathological feature of kidney fibrosis. Although fibroblasts play a predominant role in tissue fibrosis, the role of repairing tubular epithelia in tubular atrophy is unclear. We demonstrated the essential role of focal adhesion kinase (FAK)-mediated intratubular epithelial-mesenchymal transition (EMT) in the pathogenesis of tubular atrophy after severe ischemia-reperfusion injury (IRI). Actively proliferating tubular epithelia undergoing intratubular EMT were noted in the acute phase of severe IRI, resulting in tubular atrophy in the chronic phase, reflecting failed tubular repair. Furthermore, FAK was phosphorylated in the tubular epithelia in the acute phase of severe IRI, and its inhibition ameliorated both tubular atrophy and interstitial fibrosis in the chronic phase after injury. In vivo clonal analysis of single-labeled proximal tubular epithelial cells after IRI using proximal tubule reporter mice revealed substantial clonal expansion after IRI, reflecting active epithelial proliferation during repair. The majority of these proliferating epithelia were located in atrophic and nonfunctional tubules, and FAK inhibition was sufficient to prevent tubular atrophy. In vitro, transforming growth factor-ß induced FAK phosphorylation and an EMT phenotype, which was also prevented by FAK inhibition. In an in vitro tubular epithelia gel contraction assay, transforming growth factor-ß treatment accelerated gel contraction, which was suppressed by FAK inhibition. In conclusion, injury-induced intratubular EMT is closely related to tubular atrophy in a FAK-dependent manner.
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Lesión Renal Aguda/patología , Células Epiteliales/patología , Transición Epitelial-Mesenquimal , Túbulos Renales Proximales/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Animales , Atrofia , Línea Celular , Proliferación Celular , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Quinasa 1 de Adhesión Focal/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Masculino , Ratones Transgénicos , Fenotipo , Fosforilación , Ratas , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismoRESUMEN
BACKGROUND: Erythropoietin-stimulating agents (ESAs) are used to treat anemia in patients with chronic kidney disease, enabling maintenance of stable hemoglobin levels and eliminating the need for multiple transfusions. Epoetin-beta pegol (C.E.R.A.) is a continuous erythropoietin receptor activator created by integrating a large methoxy-polyethylene-glycol-polymer chain into the erythropoietin molecule, which provides it with a longer half-life. On rare occasions, cases of antibody-mediated pure red cell aplasia (PRCA) related to ESAs are reported. They are characterized by abrupt onset of severe transfusion-dependent anemia, despite ESA therapy. We herein report a case of antibody-mediated PRCA in a dialysis patient receiving C.E.R.A. CASE PRESENTATION: A 44-year-old man with end-stage renal failure had been receiving continuous ambulatory peritoneal dialysis for 2 years. C.E.R.A. was administered subcutaneously as a sole ESA once a month at the hospital since 4 years ago for the treatment of renal anemia and his hemoglobin level was well controlled at 12 g/dl. From 10 months before diagnosis, however, his hemoglobin level suddenly declined, necessitating frequent transfusions. Based on the results of a bone marrow examination and detection of anti-C.E.R.A. antibodies, the patient was diagnosed with antibody-mediated PRCA. After successful elimination of the antibodies using oral prednisolone plus cyclosporine, the patient was re-administrated C.E.R.A. intravenously, as there are few reports of antibody-mediated PRCA related to ESA using that administration route. He responded to the C.E.R.A., and his anemia dramatically improved, eliminating the need for blood transfusions. CONCLUSIONS: This is the first reported case of recovery from an antibody-mediated PRCA with C.E.R.A. after its re-administration following a reversal of the antibody. It has been suggested that the additional large pegylation chain makes C.E.R.A. less likely to trigger antibody generation than other ESAs. Following successful treatment of antibody-mediated PRCA using immunosuppressive therapy, C.E.R.A. can be re-administered intravenously to treat renal anemia.
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Anemia/tratamiento farmacológico , Anticuerpos/inmunología , Eritropoyetina/inmunología , Hematínicos/inmunología , Fallo Renal Crónico/terapia , Aplasia Pura de Células Rojas/inmunología , Adulto , Anemia/etiología , Ciclosporina/uso terapéutico , Eritropoyetina/administración & dosificación , Glucocorticoides/uso terapéutico , Hematínicos/administración & dosificación , Humanos , Inmunosupresores/uso terapéutico , Inyecciones Intravenosas , Inyecciones Subcutáneas , Fallo Renal Crónico/complicaciones , Masculino , Polietilenglicoles/administración & dosificación , Prednisolona/uso terapéutico , Aplasia Pura de Células Rojas/tratamiento farmacológico , Diálisis RenalRESUMEN
BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by mutations in the LMX1B gene and is characterized by nail dysplasia, skeletal abnormalities, and nephropathy. We herein report a case of steroid-resistant nephrotic syndrome (SRNS) prior to overt orthopedic symptoms in a patient with NPS. CASE PRESENTATION: A 24-year-old woman presented to our hospital with knee pain. She had poorly developed nails, hypoplastic patellas, dislocation of the elbows, and iliac horns in the pelvis. At the age of 7, she developed nephrotic syndrome and was diagnosed with primary focal segmental glomerulosclerosis by renal biopsy. She received long-term corticosteroid therapy with no obvious response. Her clinical course and orthopedic manifestations indicated NPS, and a genetic analysis showed a de novo mutation in the LMX1B gene (c.819 + 1G > A). Nephropathy in this case was considered to be associated with NPS. Therefore, we discontinued corticosteroids without the exacerbation of nephrotic syndrome. CONCLUSIONS: Patients with NPS may develop nephrotic syndrome prior to overt orthopedic symptoms and only show non-specific findings in renal biopsy at an early stage of NPS nephropathy. Hereditary nephrotic syndrome, often presenting as childhood-onset SRNS, may also be difficult to diagnose in patients with the following conditions: renal symptoms prior to overt extrarenal symptoms, de novo mutations, and non-specific findings in renal biopsy. Therefore, in the management of SRNS in children, we need to reconsider the possibility of hereditary diseases such as NPS even without a family history.
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Proteínas con Homeodominio LIM/genética , Síndrome de la Uña-Rótula/diagnóstico , Síndrome Nefrótico/diagnóstico , Factores de Transcripción/genética , Corticoesteroides/uso terapéutico , Femenino , Humanos , Riñón/patología , Riñón/ultraestructura , Mutación , Síndrome de la Uña-Rótula/complicaciones , Síndrome de la Uña-Rótula/genética , Síndrome de la Uña-Rótula/patología , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/etiología , Síndrome Nefrótico/genética , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
We report a case of 39-year-old man who developed tricuspid valve infective endocarditis with a complication of pulmonary embolism. He was transferred to our institution because of intermittent fever and enlargement of the vegetation of the tricuspid valve in spite of optimal antibiotics treatment. Computed tomography revealed pulmonary embolism, and transesophageal echocardiography showed a large and mobile vegetation (22×10 mm) on the tricuspid valve with moderate regurgitation. In addition, Streptococcus agalactiae was identified in blood cultures. The patient underwent surgical resection of the vegetation followed by tricuspid valve repair including De Vega's annuloplasty. Antibiotic therapy was continued for 4 weeks after surgery, and he was discharged on the 31st postoperative day. No endocarditis nor tricuspid valve dysfunction has re-occurred.
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Miocarditis/cirugía , Embolia Pulmonar/complicaciones , Insuficiencia de la Válvula Tricúspide/cirugía , Adulto , Antibacterianos/uso terapéutico , Procedimientos Quirúrgicos Cardíacos , Humanos , Masculino , Miocarditis/tratamiento farmacológico , Miocarditis/microbiología , Streptococcus agalactiae/aislamiento & purificación , Insuficiencia de la Válvula Tricúspide/microbiologíaRESUMEN
Using a comprehensive transcriptome analysis, a Z chromosome-linked chicken homolog of hemogen (cHEMGN) was identified and shown to be specifically involved in testis differentiation in early chicken embryos. Hemogen [Hemgn in mice, EDAG (erythroid differentiation-associated gene protein) in humans] was recently characterized as a hematopoietic tissue-specific gene encoding a transcription factor that regulates the proliferation and differentiation of hematopoietic cells in mammals. In chicken, cHEMGN was expressed not only in hematopoietic tissues but also in the early embryonic gonad of male chickens. The male-specific expression was identified in the nucleus of (pre)Sertoli cells after the sex determination period and before the expression of SOX9 (SRY-box 9). The expression of cHEMGN was induced in ZW embryonic gonads that were masculinized by aromatase inhibitor treatment. ZW embryos overexpressing cHEMGN, generated by infection with retrovirus carrying cHEMGN, showed masculinized gonads. These findings suggest that cHEMGN is a transcription factor specifically involved in chicken sex determination.
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Pollos/metabolismo , Proteínas Nucleares/metabolismo , Homología de Secuencia de Aminoácido , Procesos de Determinación del Sexo , Animales , Inhibidores de la Aromatasa/farmacología , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Embrión de Pollo , Cromosomas/metabolismo , ADN Complementario/genética , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Gónadas/efectos de los fármacos , Gónadas/metabolismo , Hematopoyesis/efectos de los fármacos , Hematopoyesis/genética , Humanos , Masculino , Ratones , Proteínas Nucleares/genética , Procesos de Determinación del Sexo/efectos de los fármacos , Especificidad de la EspecieRESUMEN
DMRT1 encodes a conserved transcription factor with an essential role in gonadal function. In the chicken, DMRT1 in located on the Z sex chromosome and is currently the best candidate master regulator of avian gonadal sex differentiation. We previously showed that knockdown of DMRT1 expression during the period of sexual differentiation induces feminisation of male embryonic chicken gonads. This gene is therefore necessary for proper testis development in the chicken. However, whether it is sufficient to induce testicular differentiation has remained unresolved. We show here that over-expression of DMRT1 induces male pathway genes and antagonises the female pathway in embryonic chicken gonads. Ectopic DMRT1 expression in female gonads induces localised SOX9 and AMH expression. It also induces expression of the recently identified Z-linked male factor, Hemogen (HEMGN). Masculinised gonads show evidence of cord-like structures and retarded female-type cortical development. Furthermore, expression of the critical feminising enzyme, aromatase, is reduced in the presence of over-expressed DMRT1. These data indicate that DMRT1 is an essential sex-linked regulator of gonadal differentiation in avians, and that it likely acts via a dosage mechanism established through the lack of global Z dosage compensation in birds.
Asunto(s)
Gónadas/embriología , Gónadas/metabolismo , Procesos de Determinación del Sexo , Factores de Transcripción/metabolismo , Animales , Hormona Antimülleriana/metabolismo , Aromatasa/genética , Aromatasa/metabolismo , Embrión de Pollo , Electroporación , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Factor de Transcripción SOX9/metabolismo , Testículo/embriología , Testículo/metabolismo , Factores de TiempoRESUMEN
OBJECTIVE: To evaluate the efficacy of pleurodesis using OK-432 after cardiac surgery in the neonatal period or early infancy. METHODS: We retrospectively reviewed the data of 11 consecutive patients who underwent cardiac surgery in the neonatal period or early infancy and pleurodesis using OK-432 for persistent postoperative pleural effusion in two institutions. RESULTS: The median age at surgery was 8 days (interquartile range [IR], 2-18) with a body weight of 2.84â kg (IR, 2.30-3.07). The maximum amount of pleural drainage before pleurodesis was 94.7 (IR, 60.2-107.7) ml/kg/day. Pleurodesis was initiated at postoperative day 20 (IR, 17-22) and performed in bilateral pleural spaces in seven patients and unilateral in four. The median numbers of injection were 4 (IR, 3-6) times per patient and 3 (IR, 2-3) times per pleural space. In 10 patients, pleural effusion was decreased effectively, and drainage tubes were removed without reaccumulation within 15 (IR, 12-28) days after initial pleurodesis. However, in one patient, with severe lymphedema, pleural effusion was uncontrollable, resulting in death due to sepsis. Adverse events were observed in nine patients; temporal deterioration of lung compliance and arterial blood gas occurred in two, insufficient drainage requiring new chest tube(s) in five, temporal atrial tachyarrhythmia in one, and lymphedema in four. CONCLUSIONS: Pleurodesis using OK-432 is effective and reliable for persistent postoperative pleural effusion in neonates and early infants. Most of the complications, which derived from inflammatory reactions, were temporary and controllable. However, severe lymphedema is difficult to control.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Linfedema , Derrame Pleural Maligno , Derrame Pleural , Lactante , Recién Nacido , Humanos , Picibanil/uso terapéutico , Pleurodesia/métodos , Estudios Retrospectivos , Derrame Pleural/tratamiento farmacológicoRESUMEN
Introduction: A reduced salt intake is a vital lifestyle modification in the management of hypertension. Initiatives aimed at decreasing the intake of salt are based on the preference by humans for a salt taste. Salt intake behavior appears to be affected by the balance between attraction to a low salt taste and aversion to a high salt taste. However, aversion to a high salt taste has not yet been quantitively investigated in both healthy individuals and patients with chronic kidney disease (CKD). Methods: Assessments of gustatory and aversion thresholds for salt, bitter, sour, and sweet tastes were performed using a stimulant-impregnated test strip in healthy subjects and patients with CKD. Results: In a pilot taste test of 125 healthy subjects, the number of participants with an aversive reaction increased at higher salt concentrations. The threshold for normal taste perception was arbitrarily defined as 10% NaCl, with 47.2% of healthy subjects displaying an aversive reaction. In taste tests performed by 70 patients with CKD, 10% were unable to recognize a salt taste, even at the highest concentration (20% NaCl), suggesting a significant impairment in taste perception in patients with CKD. Only 15.7% of patients with CKD exhibited a normal aversion to NaCl, whereas 78.6% showed the complete loss of aversion to salt. Conclusion: The present results confirmed the anticipated aversive response to a high salt taste in humans and demonstrated its impairment in patients with CKD, implying that patients with CKD have reduced resistance to a high salt intake.
RESUMEN
The immense public health burden of diabetic kidney disease (DKD) has led to an increase in research on the pathophysiology of advanced DKD. The present study focused on the significance of proinflammatory vascular cell adhesion molecule 1 (VCAM1)+ tubules in DKD progression. A retrospective cohort study of DKD patients showed that the percentage of VCAM1+ tubules in kidney samples was correlated with poor renal outcomes. We established an advanced DKD model by partial resection of the kidneys of db/db mice and demonstrated that it closely resembled the human advanced DKD phenotype, with tissue hypoxia, tubular DNA damage, tissue inflammation, and high tubular VCAM1 expression. Luseogliflozin ameliorated tissue hypoxia and proinflammatory responses, including VCAM1+ expression, in tubules. These findings suggest the potential of tubular VCAM1 as a histological marker for poor DKD outcomes. SGLT2 inhibitors may attenuate tissue hypoxia and subsequent tissue inflammation in advanced DKD, thereby ameliorating tubular injury.
RESUMEN
A 2-month-old girl who had supracardiac total anomalous pulmonary venous connection (Darling classification type 1b) was referred to our institution. Computed tomography showed that multiple right upper pulmonary veins drained into the vertical vein, near the entry to the superior vena cava. The common pulmonary venous chamber was located lower right than usual, and right upper pulmonary veins were far from the common chamber. We successfully performed primary sutureless repair concomitant with the Warden procedure. Postoperative computed tomography showed unobstructed pulmonary veins and superior vena cava routes, and the vertical vein between right upper and lower pulmonary veins shrank slightly.
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Venas Pulmonares , Síndrome de Cimitarra , Procedimientos Quirúrgicos sin Sutura , Femenino , Humanos , Lactante , Vena Cava Superior/anomalías , Venas Pulmonares/cirugía , Síndrome de Cimitarra/complicaciones , Síndrome de Cimitarra/diagnóstico por imagen , Síndrome de Cimitarra/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic ß-cells or proximal tubular epithelial cells through the glucose transporter, GLUT2. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of STZ-treated tubular epithelial cells in vitro showed the activation of the p53 signaling pathway. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transporters. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic ß-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo. Since the cytotoxic effects of STZ against ß-cells were not impaired by dapagliflozin, pretreatment with an SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.
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Antineoplásicos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Ratones , Animales , Estreptozocina/toxicidad , Proteína p53 Supresora de Tumor/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Riñón/metabolismo , Transducción de Señal , Antineoplásicos/farmacología , Túbulos Renales Proximales/metabolismoRESUMEN
The sericin-1 gene encoding a glue protein is expressed in the middle silk gland (MSG) of the silkworm, Bombyx mori. A member of the class III POU domain transcription factors, POU-M1, was cloned as the factor bound to the SC site of the sericin-1 promoter and has been proposed to be a positive transcription factor. In this study, we analyzed the expression pattern of the POU-M1 gene in fourth and fifth instars in comparison with the pattern of the sericin-1 gene. The POU-M1 gene was expressed strongly in the region anterior to the sericin-1-expressing portion of the silk gland at both feeding stages. As the sericin-1-expressing region expands from the posterior to middle portions of the MSG in the fifth instar, the POU-M1-expressing region retreated from the middle to anterior portion. Introduction of the expression vector of POU-M1 into the silk glands by gene gun technology repressed promoter activity of the sericin-1 gene, suggesting that POU-M1 regulates the sericin-1 gene negatively. An in vitro binding assay showed that POU-M1 bound not only to the SC site but also to other promoter elements newly detected in vivo. Another spatiotemporal specific factor MIC binds to these elements, and POU-M1 competed with MIC to bind at the -70 site essential for promoter activity. These results suggest that POU-M1 is involved in restricting the anterior boundary of the sericin-1-expressing region in the silk gland by inhibiting the binding of the transcriptional activator to the promoter elements.
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Bombyx/genética , Proteínas de Insectos/genética , Factores del Dominio POU/metabolismo , Sericinas/genética , Animales , Secuencia de Bases , Bombyx/crecimiento & desarrollo , Bombyx/metabolismo , Regulación de la Expresión Génica , Proteínas de Insectos/metabolismo , Larva/genética , Larva/metabolismo , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Alineación de Secuencia , Activación TranscripcionalRESUMEN
We present the case of a 1-year-old girl with mid-aortic syndrome due to untreated Takayasu's arteritis who developed cardiogenic shock. Enhanced computed tomography revealed long-segment occlusion of the distal thoracic aorta. We successfully performed graft interpose (10 mm in diameter) under cardiopulmonary bypass through both median sternotomy and left posterolateral thoracotomy. The thrombus was relatively small and the distal thoracic aorta was narrow over a long segment due to severely thickened intima. Follow-up computed tomography showed widely patent graft without a stenotic region in the abdominal aorta or its branches. The patient discharged ambulatory without major complications.
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Arteritis de Takayasu , Aorta , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/cirugía , Niño , Constricción Patológica , Femenino , Humanos , Lactante , Arteritis de Takayasu/complicaciones , Arteritis de Takayasu/diagnóstico por imagen , Arteritis de Takayasu/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Kidney hypertrophy is a common clinical feature in patients with diabetes and is associated with poor renal outcomes. Initial cell proliferation followed by cellular hypertrophy are considered the responsible mechanisms for diabetic kidney hypertrophy. However, whether similar responses against hyperglycemia continue in the chronic phase in diabetes is unclear. We performed lineage tracing analysis of proximal tubular epithelia using novel type 2 diabetic mice with a tamoxifen-inducible proximal tubule-specific fluorescent reporter. Clonal analysis of proximal tubular epithelia demonstrated that the labeled epithelia proliferated in type 2 diabetic mice. Based on the histological analysis and protein/DNA ratio of sorted labeled tubular epithelia, there was no evidence of cellular hypertrophy in type 2 diabetic mice. Lineage tracing and histological analyses of streptozocin-induced type 1 diabetes also revealed that cellular proliferation occurs in the chronic phase of type 1 diabetes induction. According to our study, epithelial proliferation accompanied by SGLT2 upregulation, rather than cellular hypertrophy, predominantly occurs in the hypertrophic kidney in both type 1 and type 2 diabetes. An increased number of SGLT2+ tubular epithelia may be an adaptive response against hyperglycemia, and linked to the hyper-reabsorption of sodium and glucose observed in type 2 diabetes patients.
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Proliferación Celular , Nefropatías Diabéticas/patología , Células Epiteliales/patología , Túbulos Renales Proximales/patología , Animales , Proliferación Celular/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/etiología , Modelos Animales de Enfermedad , Hipertrofia , Túbulos Renales Proximales/citología , Masculino , Transportador 2 de Sodio-Glucosa/genética , Transportador 2 de Sodio-Glucosa/metabolismo , Regulación hacia ArribaRESUMEN
Based on recent clinical trials using sodium-glucose co-transporter 2 inhibitor (SGLT2i) demonstrating the significant improvement of outcomes of diabetic kidney disease (DKD), the paradigm shift from "glomerulocentric" to "tubule centric" pathophysiology in DKD progression has been highlighted. Several responsible mechanisms for renoprotective effects by SGLT2i have been proposed recently, but the changes in proximal tubule-specific gene expression by SGLT2i in diabetic mice have not been elucidated. We report the analysis of the proximal tubular-specific pathway, demonstrating the downregulation of oxidative phosphorylation in dapagliflozin-treated db/db mice, a type 2 diabetic model. After 8-week treatment of dapagliflozin for db/db mice having a proximal tubule-specific tdTomato reporter, tdTomato-positive cells were isolated by FACS. Pathway analysis of RNA sequencing of isolated tubular epithelia revealed that oxidative phosphorylation was downregulated in dapagliflozin-treated mice. However, depletion of renal tissue ATP content in db/db mice was ameliorated by dapagliflozin administration. Pimonidazole staining demonstrated renal cortical tissue hypoxia in db/db mice, which was improved by dapagliflozin administration. This study suggests that dapagliflozin can ameliorate the excessive oxygen and ATP consumption, and subsequent tissue hypoxia in the diabetic kidney, which may explain, in part, the responsible mechanisms of the renoprotective effects of dapagliflozin.
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A full-term infant who had tricuspid atresia with transposed great arteries, a ventricular septal defect, subpulmonary stenosis with posterior malalignment of the conus septum, bicuspid pulmonary valve, and a high-takeoff left coronary artery was referred to our institution. The subpulmonary stenosis gradually progressed and cyanosis worsened. We successfully performed a Damus-Kay-Stansel procedure and a bidirectional Glenn shunt concomitant with ventricular septal defect enlargement. The conus septum was resected along with thick fibrous tissue through both semilunar valves (without ventriculotomy). Postoperative echocardiography demonstrated that both the ventricular septal defect and the subpulmonary space were enlarged effectively without semilunar valve regurgitation.
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Procedimiento de Fontan , Cardiopatías Congénitas , Defectos del Tabique Interventricular , Válvula Pulmonar , Transposición de los Grandes Vasos , Defectos del Tabique Interventricular/diagnóstico por imagen , Defectos del Tabique Interventricular/cirugía , Humanos , Lactante , Arteria Pulmonar/cirugíaRESUMEN
BACKGROUND: The long-term outcomes of a total cavopulmonary connection (TCPC) with an extracardiac conduit (ECC) for patients with apicocaval juxtaposition (ACJ) remain unclear. METHODS: A total of 38 patients with ACJ who underwent TCPC with ECC between 1998 and 2014 were enrolled in this study. For 19 patients with a superior vena cava - inferior vena cava contralateral position, a long-curved route rounding the opposite side of the apex was selected (CC group). For 11 patients with a superior vena cava-inferior vena cava ipsilateral position, a long-curved route was principally selected (IC group); however, a short, straight route was selected for 8 patients because there was sufficient space behind the ventricular apex (IS group). RESULTS: Follow-up was completed in all patients, with a mean follow-up duration of 13.2 ± 4.9 years. The angles of the caudal conduit anastomosis site measured from the frontal view of cineangiography had significantly straightened in the CC group from 1 year to 15 years (P < .05) and in the IC group from 1 year to 10 years (P < .05). There were 2 late mortalities and 6 reoperations during follow-up. Overall survival and freedom from reoperation rates at 15 years were 95% and 82%, respectively. There were no conduit-related or route-related complications such as death, reoperations, pulmonary venous obstructions, conduit obstructions, or pulmonary arteriovenous malformations in any of the groups. CONCLUSIONS: Even though chronologic geometric changes of curved ECCs were observed, TCPC with ECC for patients with ACJ can be safely applied without conduit- or route-related complications in long-term follow-up.
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Procedimiento de Fontan/métodos , Cardiopatías Congénitas/cirugía , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Corazón Univentricular/cirugíaRESUMEN
Cisplatin is a commonly used anticancer drug, but nephrotoxicity is a dose-limiting adverse effect. Recent experimental and clinical observations have demonstrated that multiple injections of cisplatin induce the transition to chronic kidney disease; however, the underlying mechanisms remain unclear. We found that multiple injections of higher doses of cisplatin in a shorter interval affected the severity of kidney injury, causing kidney fibrosis to develop at a later time point. An additional injection of cisplatin during the recovery period after a prior injury, when proximal tubule epithelia are actively proliferating, induced substantial tubular injury by inducing more severe DNA damage than that induced by a single injection. Lineage tracing analysis of proximal tubular epithelia demonstrated that the tubular epithelia that underwent multiple rounds of cell division after multiple injections of cisplatin existed at the chronic phase, and these populations often expressed vcam1 + , suggesting the induction of proinflammatory failed-repair tubular epithelia. Our study revealed that as cisplatin exerts cytotoxic effects on actively proliferating cells, additional cisplatin injections before the completion of tubular repair exacerbates kidney injury through cumulative DNA damage. Appropriate both the setting of dosage and dosing intervals, with careful monitoring, are essential to prevent nephrotoxicity of repeated cisplatin treatment in cancer patients.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Daño del ADN/efectos de los fármacos , Insuficiencia Renal Crónica/inducido químicamente , Lesión Renal Aguda/patología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Modelos Animales de Enfermedad , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica/patologíaRESUMEN
OBJECTIVES: Heterotaxy syndrome, which is often associated with atrioventricular valvar regurgitation, has been considered a risk factor for the surgical repair for Fontan candidates. The results of atrioventricular valve repair in this challenging patient population remain largely unknown. METHODS: From July, 1994 to January, 2007, 25 patients with the heterotaxy syndrome consisting of 22 right isomerism and three left isomerism presented to the Shizuoka Children's Hospital Japan with significant (3-4+) atrioventricular valvar regurgitation necessitating atrioventricular valve repair. The clinical and Doppler/echocardiographic data were retrospectively reviewed to determine the efficacy of the repair and patient outcome. RESULTS: Patients were divided into two groups on the basis of atrioventricular valvar regurgitation at the most recent follow-up: those with a successful late outcome, (0-2) and those with a poor outcome (3-4). There were 17 (67%) patients with a successful outcome and 8 (33%) with a poor outcome. The repair technique including leaflet apposition was predictive of a successful outcome (p = 0.003). Overall survival was 64% (16/25). Survival was 88.2% (15/17) for patients with a successful result versus 12.5% (1/8) for those with a poor outcome (p = 0.0007). Of the 15 survivors, 13 have reached final completion of the Fontan circulation, and two currently remain at the bi-directional Glenn shunt stage. CONCLUSION: Atrioventricular valve repair can be accomplished in this challenging patient population with excellent results. The combination of the leaflet apposition technique and the Kay suture can be performed with an excellent outcome in the majority of patients with heterotaxy syndrome, even with significant atrioventricular valvar regurgitation.