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BACKGROUND: Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4+ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN. METHODS: Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4+ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry. RESULTS: We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4+ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells. CONCLUSION: Our study identified novel aberrant DMPs in CD4+ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.
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Linfocitos T CD4-Positivos , Metilación de ADN , Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Metilación de ADN/genética , Linfocitos T CD4-Positivos/metabolismo , Femenino , Masculino , Adulto , Nefritis Lúpica/genética , Lupus Eritematoso Sistémico/genética , Epigénesis Genética/genética , Islas de CpG/genética , Estudios de Casos y Controles , Persona de Mediana Edad , BiomarcadoresRESUMEN
BACKGROUND: Liver tumor remains an important cause of cancer-related death. Nanosecond pulsed electric fields (nsPEFs) are advantageous in the treatment of melanoma and pancreatic cancer, but their therapeutic application on liver tumors need to be further studied. METHODS: Hep3B cells were treated with nsPEFs. The biological behaviors of cells were detected by Cell Counting Kit-8, 5-ethynyl-20-deoxyuridine, and transmission electron microscopy (TEM) assays. In vivo, rabbit VX2 liver tumor models were ablated by ultrasound-guided nsPEFs and radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) was used to evaluate the ablation effect. HE staining and Masson staining were used to evaluate the tissue morphology after ablation. Immunohistochemistry was performed to determine the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin at different time points after ablation. RESULTS: The cell viability of Hep3B cells was continuously lower than that of the control group within 3 days after pulse treatment. The proliferation of Hep3B cells was significantly affected by nsPEFs. TEM showed that Hep3B cells underwent significant morphological changes after pulse treatment. In vivo, CEUS imaging showed that nsPEFs could completely ablate model rabbit VX2 liver tumors. After nsPEFs ablation, the area of tumor fibrosis and the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin were decreased. However, after RFA, rabbit VX2 liver tumor tissue showed complete necrosis, but the expression of PCNA and α-smooth muscle actin did not decrease compared to the tumor group. CONCLUSIONS: nsPEFs can induce Hep3B cells apoptosis and ablate rabbit VX2 liver tumors in a non-thermal manner versus RFA. The ultrasound contrast agent can monitor immediate effect of nsPEF ablation. This study provides a basis for the clinical study of nsPEFs ablation of liver cancer.
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Actinas , Neoplasias Hepáticas , Animales , Conejos , Antígeno Nuclear de Célula en Proliferación , Antígeno Ki-67 , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , ApoptosisRESUMEN
Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia-reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Ratones , Animales , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Riñón/patología , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Fibrosis , Daño por Reperfusión/patologíaRESUMEN
Background: Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease. Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI. Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm. Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated. Methods: AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration. To further determine the function of EGR1, Egr1-/- mice were applied. Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9. Results: EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database. Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration. Further experiments affirmed that genetic inhibition of Egr1 aggravates the severity of AKI in mouse models. Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the Sox9 gene, thus promoting SOX9+ cell proliferation by activating the Wnt/ß-catenin pathway. Conclusions: Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.
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Lesión Renal Aguda , Proteína 1 de la Respuesta de Crecimiento Precoz , Túbulos Renales , Daño por Reperfusión , Factor de Transcripción SOX9 , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Animales , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Células Epiteliales/metabolismo , Humanos , Riñón/metabolismo , Riñón/patología , Túbulos Renales/metabolismo , Túbulos Renales/patología , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Regulación hacia Arriba , Vía de Señalización WntRESUMEN
Tb2.96- x Ce0.04GdxAl5O12 phosphors were synthesized through solid-state reactions. The influence of Gd3+ on the luminescence was investigated. Under the excitation at 460 nm, Tb2.96Ce0.04Al5O12 shows the characteristic emission band of Ce3+ with a peak wavelength at about 554 nm. After co-doping Gd3+ into Tb2.96Ce0.04Al5O12, the peak wavelength of the Ce3+ emission band shifts to longer wavelengths, which is induced by the increasing crystal field splitting. However, the Ce3+ emission intensity also decreases because the substitution of Tb3+ with Gd3+ causes lattice deformation and generates numerous structural and chemical defects. By comparing the light parameters of white light-emitting diodes (WLEDs) containing Y2.96Ce0.04Al5O12, Tb2.96Ce0.04Al5O12 and Tb2.81Ce0.04Gd0.15Al5O12 phosphors, we can find that the WLED containing the Tb2.81Ce0.04Gd0.15Al5O12 phosphor generates warmer light than the WLEDs containing Y2.96Ce0.04Al5O12 and Tb2.96Ce0.04Al5O12 phosphors. Moreover, the WLEDs fabricated by integrating a blue LED chip and Ce3+/Gd3+-co-doped Tb3Al5O12 phosphors show outstanding colour stability when driven under different currents.
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Mesangial cell (MC) activation and macrophage infiltration are 2 major events closely related with each other in mesangial proliferative glomerulonephritis. In the anti-Thy 1 nephritis model, macrophages mediate the damage and also the expansion of mesangium through secreting various inflammatory factors; however, in glomerular microenvironment how MCs affect macrophage activity in the presence of various stimuli have not yet been understood. In the present study, we found that resting human MCs (HMCs) constitutively expressed chemokine [C-C motif] ligand 2 (CCL-2) and interleukin (IL)-6 and induced M2 polarization of macrophages in the coculture system. HMC proliferation and migration and expression of IL-6, CCL-2, and macrophage colony-stimulating factor in HMCs were enhanced after platelet-derived growth factor (PDGF)-BB stimulation, among which CCL-2 was responsible for inducing the M2 polarization of macrophages. Furthermore, PDGF-BB-stimulated HMCs alleviated the classical activation of macrophages and drove more intensified M2 polarization of macrophages than resting HMCs did. However, lipopolysaccharide and interferon-γ (IFN-γ) stimulated HMCs maintained the M1 phenotype of cocultured macrophages. In conclusion, MCs actively participated in glomerular inflammation through influencing macrophage polarization. The interplay between MCs and infiltrated macrophages is finely modulated by secretory factors such as PDGF-BB and IFN-γ in response to the renal inflammatory microenvironment.
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Mesangio Glomerular/citología , Mesangio Glomerular/metabolismo , Glomerulonefritis/patología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Animales , Becaplermina/metabolismo , Movimiento Celular/inmunología , Polaridad Celular/inmunología , Proliferación Celular/fisiología , Células Cultivadas , Quimiocina CCL2/biosíntesis , Técnicas de Cocultivo , Humanos , Inflamación/patología , Interferón gamma/metabolismo , Interleucina-6/biosíntesis , Factor Estimulante de Colonias de Macrófagos/biosíntesis , Ratas , Ratas WistarRESUMEN
BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common adult nephrotic syndromes. Some patients with this disorder require immunosuppressive therapy. This retrospective case series was performed to assess the effects of tacrolimus (TAC) combined with Tripterygium wilfordii polyglycoside (TWG) in treating IMN. METHODS: From January 2015 to August 2016, kidney-biopsy-proven IMN patients treated with TAC in the Chinese PLA General Hospital were screened. Data were retrieved from the patients' medical records. The first efficacy evaluation index was remission rate (complete remission and partial remission), and the secondary efficacy evaluation indices included relapse rate, proteinuria, serum albumin and estimated glomerular filtration rate (eGFR). Adverse events were also assessed. RESULTS: The included patients' treatments were tacrolimus monotherapy (TAC group, n = 33), tacrolimus combined with methylprednisolone (MP) (TAC + MP group, n = 24) and tacrolimus combined with Tripterygium wilfordii polyglycoside (TAC + TWG group, n = 21). The remission rates of the TAC, TAC + MP, and TAC + TWG groups in the 10th month were 54.5, 62.5, and 85.7%, respectively (TAC + TWG group vs TAC group, P = 0.037, TAC + TWG group vs TAC + MP group, P = 0.125). Moreover, the complete remission rates of the TAC, TAC + MP, and TAC + TWG groups in the 10th month were 21.2, 20.8, and 57.1%, respectively (TAC + TWG group vs TAC group, P = 0.007, TAC + TWG group vs TAC + MP group, P = 0.012). Compared with the TAC group, the TAC + TWG group had a higher remission rate during these ten months (log-rank, P = 0.005). Compared with the TAC and TAC + MP groups, the TAC + TWG group had a higher complete remission rate (log-rank, P = 0.019 and log-rank, P = 0.005, respectively). CONCLUSION: This retrospective study showed that TAC combined with TWG may be effective for treating IMN. Further randomized controlled trials (RCTs) are needed to assess the efficacy and safety of TAC combined with TWG.
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Glomerulonefritis Membranosa/tratamiento farmacológico , Glicósidos/administración & dosificación , Extractos Vegetales/administración & dosificación , Tacrolimus/administración & dosificación , Tripterygium , Adulto , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glomerulonefritis Membranosa/sangre , Glomerulonefritis Membranosa/fisiopatología , Glicósidos/aislamiento & purificación , Humanos , Inmunosupresores , Masculino , Persona de Mediana Edad , Extractos Vegetales/aislamiento & purificación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To identify risk factors associated with succenturiate placenta and to evaluate the association between adverse pregnancy outcomes and succenturiate placenta in singleton pregnancies. STUDY DESIGN: The total population of women (n = 28,256) with singleton pregnancies who delivered in Zhangqiu City Hospital during the study period between 2002 and 2012 was reviewed. Risk factors. and adverse pregnancy outcomes were evaluated separately among women with and without succenturiate placenta by means of χ² and logistic regression analyses. RESULTS: The incidence of succenturiate placenta among women with singleton pregnancies was 1.04% (n = 294 of 28,256). Independent risk factors for succenturiate placenta were gestational age, prepregnancy BMI, pelvic infection, prior cesarean section, infertility, and preeclampsia. The succenturiate placenta was associated with a 1.076-, 1.056-, 12.076-, 1.894-, 5.217-, and 4.814-fold increased risk, respectively, as compared to pregnancies with normal cord insertion. For pregnancy outcome comparisons, cases of premature birth, low birth weight, and 5-minute Apgar score ≤ 7 were higher in cases with succenturiate placenta than in those without succenturiate placenta. The rate of cesarean section was increased. CONCLUSION: The results suggest that the incidence of succenturiate placenta increases along with an increase in pelvic infection, infertility, and preeclampsia. The condition of succenturiate placenta increases the risks for prematurity, impaired fetal growth, and cesarean delivery.
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Placenta/anomalías , Resultado del Embarazo , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Cesárea , China/epidemiología , Femenino , Edad Gestacional , Humanos , Recién Nacido de Bajo Peso , Infección Pélvica/complicaciones , Preeclampsia , Embarazo , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Crush syndrome is a common injury, the main characteristics of which include acute kidney injury. However, there is still lack of reliable animal model of crush syndrome, and it also remains controversial as to which type of fluid should be chosen as a more appropriate treatment option for prevention and treatment of acute kidney injury. METHODS: The rabbits were crushed at the lower limbs for 6 h with 36 times the body weight, which means the pressure of each leg was also 36 times the body weight. Fluid resuscitation was performed from 1 h prior to the end of the crush treatment until 24 h after the reperfusion. Tissue, blood and urine samples were collected at predetermined time points before and after reperfusion. Twelve rabbits in each group were taken for survival observation for 72 h. RESULTS: The model group showed elevated serum creatine kinase, aspartate aminotransferase, alanine aminotransferase, and K(+) level, reduced serum Ca(2+) level and Na(+) level, and increased serum creatinine and blood urea nitrogen levels, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (p < 0.05). The 0.9 % normal saline (SAL) group and SAL plus 6 % hydroxyethyl starch 130/0.4 SAL/HES group showed reduced serum creatinine and blood urea nitrogen levels (p < 0.05). The SAL/HES group also showed reduced serum IL-6 and IL-10 levels (p < 0.05). The 72 h survival rate of the SAL/HES group was higher than that of the model group (p < 0.05). CONCLUSION: The rabbit model of crush syndrome showed clinical features consistent with those of crush syndrome. There was no significant difference in the ability of preventing AKI after a crush injury between the two fluid solutions, while SAL/HES can improve the survival rate.
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Síndrome de Aplastamiento/terapia , Fluidoterapia/métodos , Derivados de Hidroxietil Almidón/uso terapéutico , Solución Salina Hipertónica/uso terapéutico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Síndrome de Aplastamiento/patología , Hemodinámica/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Sustitutos del Plasma/uso terapéutico , Conejos , Resucitación/métodos , Retículo Sarcoplasmático/efectos de los fármacos , Retículo Sarcoplasmático/metabolismo , Análisis de Supervivencia , Urodinámica/efectos de los fármacosRESUMEN
OBJECTIVE: Significant progress has been made in critical care medicine during the past several decades. However, the mortality rate is still high in patients with sepsis, especially with acute kidney injury (AKI). Mesenchymal stem cells (MSCs) possess an ability to ameliorate renal injury from ischemia-reperfusion, but it is still unknown whether they have the ability to reduce sepsis-associated AKI. METHODS: Male C57BL/6 mice underwent cecal ligation and puncture operation to induce sepsis and then received either normal saline or MSCs (1 × 10 cells intravenously) 3 h after surgery. RESULTS: Within 24 h after cecal ligation and puncture operation, the septic mice developed kidney injury and exhibited a higher mortality. Treatment with MSCs decreased serum creatinine and blood urea nitrogen levels and improved recovery of tubular function. mRNA levels of interleukin 6 (IL-6), IL-17, tumor necrosis factor α, interferon γ, CXCL1, CXCL2, CXCL5, CCL2, and CCL3 in kidney tissue were dramatically decreased after MSC treatment. Neutrophil infiltration in kidney and blood bacterial loads were attenuated after MSC injection. Moreover, mice treated with MSCs had a higher survival rate than the saline treatment group. Injected MSCs were mainly localized in the lungs, spleen, and abdominal cavity lymph node, but not in the kidneys. CONCLUSIONS: Treatment with MSCs can alleviate sepsis-associated AKI and improve survival in mice with polymicrobial sepsis. These effects may be mediated by the inhibition of IL-17 secretion and balance of the proinflammatory and anti-inflammatory states. Mesenchymal stem cells may be a potential new therapeutic agent for the prevention or reduction of sepsis-associated AKI.
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Lesión Renal Aguda/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/fisiología , Sepsis/complicaciones , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/prevención & control , Animales , Bacteriemia/terapia , Nitrógeno de la Urea Sanguínea , Ciego/cirugía , Quimiocinas/biosíntesis , Creatinina/sangre , Citocinas/biosíntesis , Interleucina-17 , Ligadura , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/fisiología , PuncionesRESUMEN
BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is a serious public health problem in China, and is primarily caused by either the Hantaan virus (HTNV) or Seoul virus (SEOV) strains. However, the causative hantavirus has only been definitively identified in a few HFRS cases, and detailed comparisons of patient data for the 2 strains are limited. METHODS: We conducted a 1-y prospective study in Heilongjiang Province, China. A total of 152 patients from 3 hospitals met the HFRS diagnostic criteria used in China. The diagnosis was further confirmed by specific immunoglobulin M to HTNV or SEOV. In addition, serum samples were tested for the presence of HTNV or SEOV using a reverse transcription-polymerase chain reaction (RT-PCR). Clinical manifestations and laboratory findings in patients with the 2 hantaviruses were subsequently compared. RESULTS: Eighty (61.1%) HTNV and 51 (38.9%) SEOV infections were identified. Fever and proteinuria, key to the diagnosis of HFRS, were observed in all patients. The clinical manifestations of hemorrhage and renal injury from SEOV infection were milder than those of HTNV infection. Interestingly, compared to patients with HTNV infection, patients with SEOV presented with a significantly longer febrile period, more normal white blood cell counts or even transient leukocytopenia, a higher incidence of liver injury related to disease severity, and a lower occurrence of the 5 typical phases of HFRS. The mortality was 6.3% in HTNV infections and 0% in SEOV infections. CONCLUSIONS: Clinical manifestations of SEOV infection appear to be milder and less typical than HTNV. This information may help us to improve the diagnosis of SEOV-infected patients.
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Virus Hantaan/aislamiento & purificación , Fiebre Hemorrágica con Síndrome Renal/virología , Virus Seoul/aislamiento & purificación , Adolescente , Adulto , Anciano , China/epidemiología , Femenino , Genotipo , Virus Hantaan/genética , Fiebre Hemorrágica con Síndrome Renal/sangre , Fiebre Hemorrágica con Síndrome Renal/diagnóstico , Fiebre Hemorrágica con Síndrome Renal/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Virus Seoul/genética , Estadísticas no ParamétricasRESUMEN
Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia(-/-) knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia(+/-) and Nfia(-/-) phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia(+/-) and Nfia(-/-) mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.
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Anomalías Múltiples/genética , Predisposición Genética a la Enfermedad , Haploidia , Factores de Transcripción NFI/genética , Malformaciones del Sistema Nervioso/genética , Anomalías Urogenitales/genética , Animales , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Embrión de Mamíferos/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Reordenamiento Génico , Humanos , Lactante , Riñón/anomalías , Riñón/embriología , Riñón/metabolismo , Masculino , Ratones , Mutación/genética , Factores de Transcripción NFI/metabolismo , Fenotipo , Médula Espinal/metabolismo , Síndrome , Uréter/anomalías , Uréter/embriología , Uréter/metabolismo , Uréter/patologíaRESUMEN
Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.