RESUMEN
OBJECTIVES: Erythropoietin (EPO) exerts tissue-protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis. METHODS: Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)-ß1 and α1(I) collagen; and the protein levels of Kelch-like ECH-associated protein 1 (Keap1) and nuclear NF-E2-related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO. RESULTS: Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF-ß1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86-positive cells (M1 macrophages), while significantly increased the number of CD206-positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value. CONCLUSIONS: These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages.
Asunto(s)
Modelos Animales de Enfermedad , Eritropoyetina , Fibrosis , Riñón , Factor de Crecimiento Transformador beta1 , Obstrucción Ureteral , Animales , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/patología , Eritropoyetina/farmacología , Eritropoyetina/uso terapéutico , Ratones , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Retraso del TratamientoRESUMEN
Joubert syndrome (JS) is a genetic neurodevelopmental disorder characterized by lower brainstem dysplasia and cerebellar vermis agenesis termed molar tooth sign (MTS), psychomotor retardation, abnormal respiratory pattern in infancy, and oculomotor abnormalities. Arima syndrome (AS), which is a severe form of JS, is characterized by severe psychomotor retardation, congenital visual impairment, progressive renal dysfunction, and lower brainstem dysplasia from early infancy. Numerous patients with AS expire in early childhood. Recently, c.6012-12T> A in the CEP290 gene was reported as a specific variant of AS. Herein, we report the cases of two siblings showing a phenotype of JS with compound heterozygous mutations (c.6012-12T > A / c.5924delT) in the CEP290 gene. The older sister (aged 19 years) had hypotonia, hypertelorism, and anteverted nares since birth. As a neonate, she developed a transient abnormal respiratory pattern and nystagmus, and brain magnetic resonance imaging (MRI) showed MTS. The younger sister (aged 13 years) exhibited mild hypotonia and pendular nystagmus as a neonate; MRI revealed MTS. Both sisters had psychomotor retardation, oculomotor dysfunction, and bilateral renal cysts with normal renal function. They can walk and have simple conversation. They do not meet the diagnostic criteria for AS, and their symptoms were milder than those of previously reported cases with this specific mutation. This report indicates the expanding spectrum of the CEP290 variant.
Asunto(s)
Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Poliquísticas , Preescolar , Femenino , Humanos , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Cerebelo/patología , Proteínas del Citoesqueleto/genética , Anomalías del Ojo/diagnóstico por imagen , Anomalías del Ojo/genética , Hipotonía Muscular , Fenotipo , Enfermedades Renales Poliquísticas/patología , Retina/anomalías , HermanosRESUMEN
Vascular lesions are symptomatic of lifestyle-related diseases and include blood clots, coarctations, aneurysms, and apoplexy. Furthermore, increased blood vessel permeability is usually observed in tumors. To develop therapeutic drugs treating vascular lesions and tumors, methods with which the vascular abnormalities can be readily assessed in experimental animals are necessary. In this paper, a laboratory-size magnetic resonance imaging (MRI) system with permanent magnets, a compact-type MRI, was used to assess vascular abnormalities. Blood vessels in the head of a mouse were clearly visualized with the compact-type MRI in combination with gadolinium-diethylenetriamine-N,N,N',Nâ³,Nâ³-pentaacetic acid chelate (Gd-DTPA)-linked dextran (Gd-Dex) as blood pool contrast agents. The rat middle cerebral artery was imaged, and artery occlusion was identified. The difference between normal and occluded rats became more apparent upon intravenous injection of sodium nitroprusside, a nitric oxide (NO) donor. The system also visualized poor circulation in a rat saphenous artery by femoral artery occlusion. In a tumor-bearing mouse, a compact-type MRI visualized accumulation of Gd-Dex similar to that of small molecular Gd-DTPA, in the rim of tumor. Gd-Dex accumulation was more consistent than that of Gd-DTPA. Tumor vasculature was characterized by estimating the plasma-to-tumor interstitial tissue transfer constant, Ktrans, of Gd-Dex and fractional plasma volume, Vp, using image data. These results demonstrate the efficacy of a compact-type MRI in combination with Gd-Dex for vascular abnormality assessment in both mice and rats.
Asunto(s)
Medios de Contraste , Dextranos , Animales , Ratones , Ratas , Gadolinio , Gadolinio DTPA , Imagen por Resonancia Magnética , Donantes de Óxido Nítrico , Espectroscopía de Resonancia MagnéticaRESUMEN
BACKGROUND: Urinary liver-type fatty acid-binding protein (uL-FABP) has recently been identified as a biomarker for kidney injury. uL-FABP excretion in pediatric relapsing nephrotic syndrome and tubular dysfunction, however, has not been reported previously. METHODS: We measured uL-FABP level in children with steroid-sensitive nephrotic syndrome (SSNS), in those with tubular dysfunction, and in control subjects. RESULTS: uL-FABP was markedly increased in relapsing SSNS (median, 30.3 µg/gCr; range, 12.6-171.0 µg/gCr; n = 13), and also in the tubular dysfunction group (median, 164.8 µg/gCr; range, 41.6-834.5 µg/gCr; n = 7), compared with the control subjects (median, 3.0 µg/gCr; range, 1.1-13.9 µg/gCr; n = 21). uL-FABP level was significantly correlated with urinary protein excretion in the SSNS group, and in the total group. Additionally, in the SSNS group, elevated uL-FABP in the relapsing stage returned to a level similar to that in the control group on remission of NS. In the tubular dysfunction group, uL-FABP was significantly correlated with urinary ß2-microglobulin. CONCLUSION: Urinary protein amount, and the ability of the proximal tubules to reabsorb low-molecular-weight proteins, should also be considered when evaluating the clinical significance of uL-FABP as a biomarker for kidney injury in children.
Asunto(s)
Biomarcadores/orina , Proteínas de Unión a Ácidos Grasos/orina , Túbulos Renales Proximales/fisiopatología , Síndrome Nefrótico/metabolismo , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Urinálisis/métodos , Adulto JovenRESUMEN
To date, there have been a very limited number of case reports on combined Alport syndrome (AS) and Klinefelter syndrome (KS). We herein describe the case of a 9-month-old boy diagnosed with concomitant AS and KS. KS was detected on chromosomal analysis of the amniotic fluid, and hematuria/proteinuria was identified in urinary screening at 6 months of age. Renal biopsy indicated AS, with complete deficit of the α5 chain of type IV collagen in the glomerular basement membranes. On genetic analysis for AS, de novo homozygote mutation (c.3605-2a > c) was seen in the gene encoding α5 chain of type IV collagen (COL4A5) on the X chromosomes of maternal origin. This is the first case report of combined AS and KS diagnosed during infancy, and it indicates the need to consider the concurrent existence of these two disorders in infants with urine abnormalities, even in the absence of a family history.
Asunto(s)
Riñón/patología , Síndrome de Klinefelter/complicaciones , Nefritis Hereditaria/complicaciones , Antagonistas de Receptores de Angiotensina/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Colágeno Tipo IV/genética , Humanos , Lactante , Irbesartán , Masculino , Mutación , Nefritis Hereditaria/diagnóstico , Nefritis Hereditaria/tratamiento farmacológico , Tetrazoles/uso terapéuticoRESUMEN
HSCT-associated thrombotic microangiopathy (TA-TMA) is a severe complication with a poor prognosis. Recently, it has been reported that complement system dysregulation, such as CFH autoantibodies and deletions CFH-related genes 3 and 1, induced TA-TMA. In addition, C4d-positive renal arterioles are both a good marker of complement system activation and a useful diagnostic tool for TA-TMA. Because dysregulation of the complement system is associated with TA-TMA, the complement system might be a therapeutic target, such as eculizumab, a terminal complement inhibitor. Herein, we describe an eight-yr-old boy who developed TA-TMA accompanied by severe renal dysfunction. His renal specimen showed diffuse C4d deposition in the renal arterioles, which is consistent with TA-TMA. Although the patient gradually improved without eculizumab, renal arteriolar C4d staining in sample with TA-TMA shows the complement system activation and may guide the target therapy using the eculizumab.
Asunto(s)
Complemento C4b/química , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Fragmentos de Péptidos/química , Arteria Renal/metabolismo , Microangiopatías Trombóticas/etiología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , Biopsia , Niño , Inactivadores del Complemento/química , Humanos , Riñón/inmunología , Leucemia Mieloide Aguda/etiología , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Pronóstico , Inducción de Remisión , Microangiopatías Trombóticas/inmunología , Resultado del TratamientoRESUMEN
Mitochondrial renal disease is one of the important causes of end-stage renal disease in children and its incidence may be underestimated. We here describe the case of a 13-year-old girl who was diagnosed with mitochondrial disease (MD) accompanied by IgA nephropathy (IgAN). She presented with persistent proteinuria, short stature, and hearing defect, and her younger sister had the same symptoms. Renal biopsy indicated mild focal segmental mesangial proliferation with dominant mesangial IgA deposition on immunofluorescence. Electron microscopy showed marked proliferation of abnormal mitochondria in the proximal tubular cells. Enzyme activity of the mitochondrial respiratory chain complex I and IV in cultured skin fibroblasts was significantly decreased. This case indicated the possible co-occurrence of IgAN and MD. Underlying MD should be considered in patients with urine abnormalities, especially in those with multiple organ involvement.
Asunto(s)
Glomerulonefritis por IGA/etiología , Enfermedades Mitocondriales/complicaciones , Adolescente , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biopsia , Compuestos de Bifenilo/uso terapéutico , Enalapril/uso terapéutico , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/tratamiento farmacológico , Humanos , Irbesartán , Túbulos Renales Proximales/patología , Microscopía Electrónica , Mitocondrias/patología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/tratamiento farmacológico , Tetrazoles/uso terapéuticoAsunto(s)
Lesión Renal Aguda/complicaciones , Uréter/anomalías , Obstrucción Ureteral/congénito , Obstrucción Ureteral/complicaciones , Lesión Renal Aguda/diagnóstico , Niño , Cistitis/complicaciones , Cistitis/diagnóstico , Femenino , Humanos , Nefrotomía/métodos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Uréter/cirugía , Obstrucción Ureteral/diagnóstico , Obstrucción Ureteral/cirugíaRESUMEN
We herein present a case of a 14-year-old boy with the histological features of coexisting membranous nephropathy (MN) and IgA nephropathy (IgAN). Asymptomatic hematuria/proteinuria was initially detected in school urinary screening, with treatments including oral corticosteroids leading to complete remission. Cases of coexisting MN and IgAN are very rare among the pediatric population; however, the overlap of these two nephropathies does not always imply a deleterious clinical outcome in pediatric cases.
Asunto(s)
Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/patología , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/patología , Adolescente , Hematuria/etiología , Humanos , Masculino , Proteinuria/etiologíaRESUMEN
UNLABELLED: Newborn screening studies indicate the expected high incidence of later-onset Fabry disease with silent Fabry nephropathy while, with recent improved clinical care of premature infants, children with congenital oligonephropathy caused by premature embryonal development of the kidney are thought to be increasing. However, the coexistence of Fabry nephropathy and oligonephropathy has not been reported previously. We present the case of a 13-year-old boy who was diagnosed with Fabry nephropathy accompanied with histological features of oligonephropathy. He was born as a preterm baby, and a renal biopsy was performed because of mild renal dysfunction and mild proteinuria. He had neither characteristic early symptoms nor a family history of Fabry disease. Histologic findings demonstrated diffuse global enlargement and foamy change of podocytes with markedly decreased number and enlargement of the glomeruli. Both his plasma and leukocyte α-galactosidase A (GLA) activities were markedly decreased, and the plasma globotriaosylsphingosine and urine globotriaosylceramide levels were increased. Gene analysis revealed a missense mutation, R112H, in the GLA gene, which had been reported in the later-onset phenotype of Fabry patients. He is now under treatment with enzyme replacement therapy and an angiotensin-converting enzyme inhibitor. CONCLUSION: This case indicated the possible co-occurrence of Fabry nephropathy and oligonephropathy. For early diagnosis and timely management, careful examinations for proteinuria and renal function, in addition to establishing an effective screening system for Fabry disease, will be necessary.
Asunto(s)
Enfermedad de Fabry/patología , Enfermedades Renales/patología , Glomérulos Renales/patología , Adolescente , Diagnóstico Diferencial , Enfermedad de Fabry/enzimología , Glucolípidos/sangre , Humanos , Enfermedades Renales/enzimología , Masculino , Mutación Missense , Esfingolípidos/sangre , Trihexosilceramidas/orina , alfa-Galactosidasa/sangre , alfa-Galactosidasa/genéticaRESUMEN
BACKGROUND: Hypoxic gas ventilation therapy has recently been performed to prevent post-birth increased pulmonary blood flow in cases of congenital heart diseases with increased pulmonary blood flow. However, how the oxygen supply to the tissues changes during breathing a hypoxic gas mixture, remains unknown. The changes in cerebral oxygen saturation and blood supply during hypoxic gas ventilation therapy using a nitrogen gas mixture were studied. METHODS AND RESULTS: Cerebral regional oxygen saturation (cerebral rSO(2)) was measured by near-infrared spectroscopy, and changes in middle cerebral artery (MCA) blood flow and an index of vascular resistance (RI) were assessed in 8 consecutive patients having congenital heart diseases with increased pulmonary blood flow. In all patients, urinary volume increased significantly, and the respiratory rate showed a clear decrease. Percutaneous oxygen saturation showed no significant change. The average of cerebral rSO(2) was 67.3% before hypoxic gas ventilation, but increased to 69.4%, 69.1%, and 70.7% within 1, 12, and 24 h after initiation of treatment, respectively. MCA blood flow significantly increased in the diastolic phase, and RI significantly improved from 0.80 to 0.68 within 12 h after initiation of therapy. CONCLUSIONS: These results indicate that hypoxic gas ventilation therapy does not decrease cerebral oxygen saturation, but safely improves the cerebral blood supply in cases of congenital heart diseases with increased pulmonary blood flow.
Asunto(s)
Velocidad del Flujo Sanguíneo , Circulación Cerebrovascular , Síndrome del Corazón Izquierdo Hipoplásico/sangre , Nitrógeno/administración & dosificación , Oxígeno/sangre , Síndromes del Arco Aórtico/sangre , Coartación Aórtica/sangre , Análisis de los Gases de la Sangre , Cardiopatías Congénitas/sangre , Humanos , Recién Nacido , Pulmón/irrigación sanguínea , Arteria Cerebral Media , Oxígeno/administración & dosificación , Espectroscopía Infrarroja Corta , Resistencia VascularRESUMEN
BACKGROUND: Matrix metalloproteinases (MMPs) contribute to extracellular remodeling in Kawasaki disease (KD). MMP-9 is an essential vasculature-remodeling factor but its role in the vascular lesions of KD is not understood. This study focused on MMP-9 regulation via cytokines in endothelial cells (ECs). METHODS AND RESULTS: Plasma and peripheral blood mononuclear cells were obtained from 30 KD patients, and 15 non-febrile and 25 febrile children. Plasma MMP-1, -2, -9, and tissue inhibitor of MMP (TIMP)-1 and -2 were measured by 2-step sandwich ELISA. Immunohistology was performed on coronary arterial lesions (CAL) from a patient who died of KD in the acute phase. MMP-9 mRNA expression in human umbilical ECs (HUVECs) treated with plasma or cytokines, and in mononuclear cells was measured by semi-quantitative reverse transcription-polymerase chain reaction. Plasma MMP-1, -2 and TIMP-2 levels were normal for KD. Plasma MMP-9 and TIMP-1 levels increased during the acute phase of the disease (P<0.001 vs each control). MMP-9 stained diffusely in CAL. MMP-9 mRNA levels were higher in HUVECs treated with plasma in the acute and convalescent phases. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha stimulated MMP-9 expression, whereas interferon (IFN)-gamma suppressed it. There was no MMP-9 mRNA elevation in mononuclear cells. CONCLUSIONS: ECs are a source of MMP-9 in the vascular lesions of KD. MMP-9 is regulated by cytokines IL-1beta, IL-6, TNF-alpha and IFN-gamma.
Asunto(s)
Vasos Sanguíneos/patología , Endotelio Vascular/enzimología , Metaloproteinasa 9 de la Matriz/análisis , Síndrome Mucocutáneo Linfonodular/patología , Vasos Sanguíneos/enzimología , Preescolar , Vasos Coronarios , Citocinas/fisiología , Células Endoteliales , Femenino , Fiebre , Humanos , Lactante , Masculino , Metaloproteinasa 9 de la Matriz/genética , Síndrome Mucocutáneo Linfonodular/enzimología , Venas Umbilicales/citologíaRESUMEN
BACKGROUND: Recent studies showed that serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) represents a novel, sensitive, specific biomarker for early detection of acute kidney injury. However, the clinical significance of measuring serum and urinary NGAL on chronic renal diseases remains unclear. METHODS: In this study, we measured serum and urinary NGAL levels in patients with several common pediatric renal diseases such as renal dysfunction (estimated glomerular filtration rate < 90 mL/min/1.73 m(2)), proliferative glomerulonephritis, steroid-resistant and steroid-sensitive nephrotic syndrome, and tubular dysfunction. RESULTS: Urinary NGAL level was significantly increased compared with the control in all of these disease groups except in patients with a remission stage of steroid-sensitive nephrotic syndrome, although a significant increase in serum NGAL level was observed in the renal dysfunction group only. Both serum and urinary NGAL levels showed significant inverse correlations with an estimated glomerular filtration rate in the analysis with total subjects, and also in the analysis with the renal dysfunction group in urinary NGAL. In proteinuric patients, the extent of proteinuria significantly correlated with urinary NGAL level. In patients with tubular dysfunction, the increase of urinary NGAL level was remarkable compared with the other disease groups. CONCLUSION: These results indicated that urinary NGAL level is a better biomarker for chronic renal diseases in children than serum NGAL level, although multiple pathological mechanisms should be considered in evaluating these NGAL values.
Asunto(s)
Proteínas de Fase Aguda/orina , Glomerulonefritis/diagnóstico , Lipocalinas/sangre , Lipocalinas/orina , Síndrome Nefrótico/diagnóstico , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas/orina , Insuficiencia Renal Crónica/diagnóstico , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Niño , Preescolar , Tasa de Filtración Glomerular , Glomerulonefritis/sangre , Glomerulonefritis/orina , Glomerulonefritis Membranoproliferativa/sangre , Glomerulonefritis Membranoproliferativa/diagnóstico , Glomerulonefritis Membranoproliferativa/orina , Humanos , Lactante , Lipocalina 2 , Masculino , Síndrome Nefrótico/sangre , Síndrome Nefrótico/orina , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/orina , Adulto JovenRESUMEN
We report on a 6-year-old boy with nephrotic syndrome (NS) who developed Wernicke's encephalopathy (WE) concomitantly with posterior reversible encephalopathy syndrome (PRES). In this case, the recurrence of encephalopathy with different causes made his clinical picture complex, and the follow-up findings of magnetic resonance imaging (MRI) were critically useful for the adequate diagnosis and timely management of the patient. This case suggests the need to consider WE as a possible serious complication in patients with NS, and also emphasizes the usefulness of MRI in the diagnosis of WE, especially in pediatric cases with complex clinical symptoms.
Asunto(s)
Síndrome Nefrótico/complicaciones , Encefalopatía de Wernicke/complicaciones , Niño , Epilepsia Generalizada/complicaciones , Humanos , Imagen por Resonancia Magnética , Masculino , Lóbulo Occipital/patología , Nutrición Parenteral Total , Síndrome de Leucoencefalopatía Posterior , Recurrencia , Lóbulo Temporal/patología , Tiamina/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Encefalopatía de Wernicke/diagnóstico , Encefalopatía de Wernicke/fisiopatologíaRESUMEN
OBJECTIVE: This study aims to investigate the changes in renal function and levels of urinary biomarkers before and after cardiac angiography in children with congenital heart disease (CHD). SETTING: Children with CHD are at a risk for kidney injury during contrast exposure in cardiac angiography. OUTCOME MEASURES: We measured urinary protein, albumin, N-acetyl-ß-D-glucosaminidase (NAG), ß2-microglobulin (BMG), and liver-type fatty acid-binding protein (L-FABP) levels, as well as serum creatinine and cystatin C levels, before and after cardiac angiography in 33 children with CHD. RESULTS: No significant decrease was noted in either the creatinine-based or cystatin C-based estimated glomerular filtration rate at 24 hours after angiography compared with that before angiography. Urinary protein, NAG, BMG, and L-FABP levels were significantly increased at 24 hours after angiography, all of which returned to baseline levels at more than 7 days after angiography. An increase in urinary level of protein, albumin, NAG, or BMG was mostly associated with increased urinary L-FABP level. An increase in both urinary BMG and L-FABP, but not that in urinary L-FABP alone, was associated with increased levels of urinary protein and NAG, as well as the greater dose of contrast media. CONCLUSIONS: Transient increases of kidney injury biomarkers following cardiac angiography are not necessarily associated with the impairment of renal function in a short time period; however, the increase in urinary protein, albumin, NAG, or BMG level may indicate greater stresses to the kidneys than the increase in urinary L-FABP alone in children with CHD.
Asunto(s)
Acetilglucosaminidasa/orina , Lesión Renal Aguda/inducido químicamente , Albuminuria/inducido químicamente , Medios de Contraste/efectos adversos , Angiografía Coronaria/efectos adversos , Proteínas de Unión a Ácidos Grasos/orina , Cardiopatías Congénitas/diagnóstico por imagen , Riñón/efectos de los fármacos , Microglobulina beta-2/orina , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/orina , Adolescente , Factores de Edad , Albuminuria/diagnóstico , Albuminuria/fisiopatología , Albuminuria/orina , Biomarcadores/orina , Niño , Femenino , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Regulación hacia Arriba , Urinálisis , Adulto JovenRESUMEN
BACKGROUND: The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signalling pathway involved in the production of proinflammatory and profibrotic mediators. Previous reports indicated the role of p38 MAPK activation in renal fibrosis. METHODS: We administered a selective p38 alpha MAPK inhibitor, FR167653, in a mouse model of unilateral ureteral obstruction (UUO) during the late stage (Days 7-14) after UUO, and the kidneys were examined at Day 14. p38 and phospho-p38 MAPK protein levels, the degree of renal fibrosis, the degree of myofibroblast accumulation and macrophage infiltration, and mRNA levels for TGF-beta1 and alpha1(I) collagen in the kidneys were assessed. RESULTS: FR167653 treatment caused marked decreases in phospho-p38 MAPK levels along with decreased fibrosis at Day 14 after UUO. Although myofibroblast accumulation and alpha1(I) collagen mRNA level were decreased, no significant change was observed in the number of interstitial macrophages and TGF-beta1 mRNA level with FR167653 treatment. CONCLUSIONS: These results suggest that p38 MAPK blockade is an appealing therapeutic target, even after the emergence of established fibrosis.
Asunto(s)
Enfermedades Renales/prevención & control , Obstrucción Ureteral/complicaciones , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Secuencia de Bases , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Cartilla de ADN/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibrosis , Enfermedades Renales/enzimología , Enfermedades Renales/etiología , Enfermedades Renales/patología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Macrophages have classically been recognized as key players that may promote renal fibrosis. However, several recent studies have suggested a beneficial anti-fibrotic role of infiltrating macrophages that acts to preserve renal architecture in the progressive renal scarring associated with obstructive nephropathy. Furthermore, recent investigations indicate a role for macrophages in both inflammation and repair during disease processes and this has superseded the classical injurious view of macrophages. As a result, the exact role of interstitial macrophages upon various facets of renal fibrosis is an important challenge that needs to be addressed. In this article, we discuss the possible beneficial anti-fibrotic role of infiltrating macrophages in obstructive nephropathy and discuss the potential mechanisms that may regulate the effect of macrophages upon renal interstitial fibrosis.
Asunto(s)
Riñón/patología , Macrófagos/patología , Obstrucción Ureteral/patología , Animales , Fibrosis , Humanos , Enfermedades Renales/patología , FenotipoRESUMEN
We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on macrophages in renal fibrosis. Fourteen days after the induction of unilateral ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the Agtr1 gene (Agtr1(-/-)) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtr1(+/+) marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes - including TGF-beta1, alpha1(I) collagen, and alpha1(III) collagen - was substantially higher in the obstructed kidneys of mice with Agtr1(-/-) marrow than in those with Agtr1(+/+) marrow at day 14 but not at day 5 of UUO. Mice with Agtr1(-/-) marrow were characterized by reduced numbers of peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo assays revealed a significantly impaired phagocytic capability in Agtr1(-/-) macrophages. In vivo treatment of Agtr1(+/+) mice with losartan reduced phagocytic capability of Agtr1(+/+) macrophages to a level comparable to that of Agtr1(-/-) macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone marrow-derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.
Asunto(s)
Células Madre Hematopoyéticas/fisiología , Enfermedades Renales/metabolismo , Riñón/patología , Macrófagos/metabolismo , Receptores de Angiotensina/metabolismo , Animales , Trasplante de Médula Ósea , Movimiento Celular/fisiología , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Fibrosis , Enfermedades Renales/patología , Macrófagos/citología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis , Receptor de Angiotensina Tipo 1 , Receptores de Angiotensina/genética , Estallido Respiratorio , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1 , Obstrucción UreteralRESUMEN
Recent findings in stem cell research have demonstrated multi-lineage plasticity of bone marrow cells, and also the contribution of hematopoietic bone marrow stem cells to the regeneration of injured organs including the kidney. These findings suggested the possibility of the use of granulocyte colony-stimulating factor (G-CSF) as a therapeutic option to regenerate injured organs. Recently, several studies regarding the effect of G-CSF on renal function have been reported in mouse models of acute renal failure. This series of experiments provided potentially important information regarding the treatment of patients with renal injury. This review summarizes the possible actions of G-CSF on the kidney, especially during acute tubular injury caused by toxic or ischemic insults.