RESUMEN
Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.
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Dependovirus , Terapia Genética , Vectores Genéticos , Animales , Dependovirus/genética , Ratones , Terapia Genética/métodos , Vectores Genéticos/genética , Humanos , Células Endoteliales/metabolismo , Glomérulos Renales/patología , Glomerulonefritis/terapia , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/genética , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunologíaRESUMEN
Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.
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Biomarcadores , Humanos , Biomarcadores/orina , Biomarcadores/sangre , Niño , Masculino , Femenino , Preescolar , Adolescente , Diagnóstico Precoz , Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Enfermedades Renales/sangre , Inflamación , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , LactanteRESUMEN
WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Glomérulos Renales , Podocitos , Transducción de Señal , Análisis de la Célula Individual , Transcriptoma , Proteínas WT1 , Animales , Podocitos/metabolismo , Podocitos/patología , Proteínas WT1/metabolismo , Proteínas WT1/genética , Humanos , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/irrigación sanguínea , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ratones , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Modelos Animales de Enfermedad , Mutación , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Adrenomedulina/genética , Adrenomedulina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Comunicación Celular , Células CultivadasRESUMEN
We evaluated the concentration of AT2R antibodies in 136 patients with primary and secondary glomerular diseases: membranous nephropathy (n = 18), focal and segmental glomerulosclerosis (n = 25), systemic lupus erythematosus (n = 17), immunoglobulin A (IgA) nephropathy (n = 14), mesangial (non-IgA) proliferative nephropathy (n = 6), c-ANCA vasculitis (n = 40), perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) vasculitis (n = 16), and compared it with a healthy control group (22 patients). Serum creatinine levels, proteinuria, serum albumin, and total protein concentrations were prospectively recorded for 2 years. The mean levels of AT2R antibodies in the lupus nephropathy group were significantly higher compared to the control group, 64.12 ± 26.95 units/mL and 9.72 ± 11.88 units/mL, respectively. There was no association between this level and the clinical course of the disease. The AT2R levels in other kinds of glomerular disease were no different from the control group. We found significant correlations between AT1R and AT2R in patients with membranous nephropathy (r = 0.66), IgA nephropathy (r = 0.61), and c-ANCA vasculitis (r = 0.63). Levels of AT2R antibodies in systemic lupus erythematosus are higher compared to other types of glomerulonephritis, vasculitis, and a healthy control group. Levels of AT2R antibodies correlate with AT1R antibodies in the groups of patients with membranous nephropathy, IgA nephropathy, and c-ANCA vasculitis. These kinds of AT2R antibodies have a stimulative effect on AT2R, but we have not found the influence of these antibodies on the clinical course of glomerular diseases.
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Autoanticuerpos , Receptor de Angiotensina Tipo 2 , Humanos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Receptor de Angiotensina Tipo 2/inmunología , Receptor de Angiotensina Tipo 2/metabolismo , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Anciano , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/sangre , Glomerulonefritis/inmunología , Glomerulonefritis/sangre , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/sangre , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Nefritis Lúpica/inmunología , Receptor de Angiotensina Tipo 1/inmunología , Adulto Joven , Enfermedades Renales/inmunologíaRESUMEN
The etiology and pathological complexity of acute kidney injury (AKI) pose great challenges for early diagnosis, typing, and personalized treatment. It is an important reason for poor prognosis and high mortality of AKI. In order to provide a relatively noninvasive diagnostic and typing method for AKI, we proposed the pathological changes of albumin permeability after glomerular injury and reabsorption efficiency after tubular injury as potential entry points. Thus, a renal tubule labeling fluorescent dye which features albumin concentration-related fluorescence intensity was used to fit these pathological changes. Utilizing this fluorescence assay, we realized urinary tract obstruction imaging as early as 12 h after morbidity. For glomerular and tubular injury discrimination, compared to a healthy control, membranous nephropathy as a representative glomerular injury resulted in enhanced fluorescence intensity of the kidney due to increased albumin penetration, while renal tubular injury caused insufficient dye reabsorption to exhibit weakened fluorescence intensity. The significant differences demonstrated the feasibility of this approach for fluorescence imaging-based AKI typing in vivo.
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Lesión Renal Aguda , Colorantes Fluorescentes , Glomérulos Renales , Túbulos Renales , Animales , Túbulos Renales/patología , Túbulos Renales/lesiones , Túbulos Renales/metabolismo , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Colorantes Fluorescentes/química , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/lesiones , Fluorometría/métodos , Ratones , Imagen Óptica , Humanos , MasculinoRESUMEN
Jiang et al. show that zinc finger FYVE-type containing 21, a Rab5 effector in glomerular endothelial cells is involved in the maintenance of glomerular filtration barrier homeostasis through the stabilization of activated endothelial nitric oxide synthase on subcellular vesicles. The study demonstrates that zinc finger FYVE-type containing 21 could modulate the levels of caveolin-1 in glomerular endothelial cells using vesicle-based trafficking, thereby supporting endothelial nitric oxide synthase activity. The authors provide evidence that decreased zinc finger FYVE-type containing 21 expression in glomerular endothelial cells could play a role in aging-related glomerular filtration barrier dysfunction.
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Envejecimiento , Caveolina 1 , Células Endoteliales , Óxido Nítrico Sintasa de Tipo III , Envejecimiento/metabolismo , Envejecimiento/fisiología , Humanos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Caveolina 1/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Animales , Barrera de Filtración Glomerular/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Glomérulos Renales/metabolismo , Riñón/fisiopatología , Riñón/metabolismo , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismoAsunto(s)
Glomerulonefritis por IGA , Glomeruloesclerosis Focal y Segmentaria , Humanos , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/clasificación , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/clasificación , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomérulos Renales/patología , BiopsiaRESUMEN
Objectives: To explore the therapeutic effects of M2 macrophages in diabetic nephropathy (DN) and their mechanism.Methods: We infused M2 macrophages stimulated with IL-4 into 10-week-old db/db mice once a week for 4 weeks through the tail vein as M2 group. Then we investigated the role of M2 macrophages in alleviating the infammation of DN and explored the mechanism.Results: M2 macrophages hindered the progression of DN, reduced the levels of IL-1ß (DN group was 34%, M2 group was 13%, p < 0.01) and MCP-1 (DN group was 49%, M2 group was 16%, p < 0.01) in the glomeruli. It was also proven that M2 macrophages alleviate mesangial cell injury caused by a high glucose environment. M2 macrophage tracking showed that the infused M2 macrophages migrated to the kidney, and the number of M2 macrophages in the kidney reached a maximum on day 3. Moreover, the ratio of M2 to M1 macrophages was 2.3 in the M2 infusion group, while 0.4 in the DN group (p < 0.01). Mechanistically, M2 macrophages downregulated Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 in mesangial cells.Conclusions: Multiple infusions of M2 macrophages significantly alleviated inflammation in the kidney and hindered the progression of DN at least partially by abrogating the M1/M2 homeostasis disturbances and suppressing the JAK2/STAT3 pathway in glomerular mesangial cells. M2 macrophage infusion may be a new therapeutic strategy for DN treatment.
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Nefropatías Diabéticas , Janus Quinasa 2 , Macrófagos , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Janus Quinasa 2/metabolismo , Nefropatías Diabéticas/metabolismo , Factor de Transcripción STAT3/metabolismo , Ratones , Macrófagos/metabolismo , Masculino , Células Mesangiales/metabolismo , Modelos Animales de Enfermedad , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Quimiocina CCL2/metabolismo , Ratones Endogámicos C57BL , Interleucina-1beta/metabolismoRESUMEN
The significance of glomerular IgM deposit intensity in IgA Nephropathy (IgAN) remained ambiguous and requires further research. Patients with biopsy-proven IgAN in our hospital from January 2018 to May 2023 were recruited into this retrospective single-center study. Patients who presented with positive IgM deposit were included in IgM + cohort while patients with negative IgM deposit were included in IgM- cohort. Of the IgM+, patients whose IF intensity of IgM deposits exceeded 1+ formed IgM-H cohort while patients whose IF intensity of IgM deposits was equal to 1+ consisted IgM-L cohort. Pairwise comparisons were performed among these cohorts to determine clinical disparities, following the propensity score matching process. Among 982 IgAN patients, 539 patients presented with positive IgM deposit. The Kaplan-Meier analysis showed that the IgM deposit did not contribute adversely to the outcomes (eGFR decreased from the baseline ≥ 50% continuously or reached end-stage renal disease). However, the Cox regression analysis showed that increased intensity of IgM deposit was an independent risk factor (p = 0.03) in IgM+. The IgM-H exhibited more pronounced segmental glomerulosclerosis (p = 0.02) than the IgM-L, which may also be associated more directly with higher urine protein levels (p = 0.02). Moreover, our generalized linear mixed model demonstrated a remarkably higher urine albumin/creatinine ratio (p < 0.01) and serum creatinine (p = 0.04) levels as well as lower serum albumin (p < 0.01) level in IgM-H persistently during the 5-year follow-up. This study concluded that increased intensity of glomerular IgM deposits may contribute adversely to clinicopathologic presentation and outcome in those IgM + patients.
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Tasa de Filtración Glomerular , Glomerulonefritis por IGA , Inmunoglobulina M , Glomérulos Renales , Humanos , Inmunoglobulina M/sangre , Masculino , Glomerulonefritis por IGA/inmunología , Femenino , Estudios Retrospectivos , Adulto , Estudios de Seguimiento , Glomérulos Renales/patología , Glomérulos Renales/inmunología , Persona de Mediana Edad , Factores de Riesgo , Fallo Renal Crónico/etiología , Fallo Renal Crónico/inmunología , Estimación de Kaplan-Meier , Progresión de la Enfermedad , Biopsia , Relevancia ClínicaRESUMEN
Diabetic kidney disease (DKD) is a microvascular complication of diabetes, and glomerular endothelial cell (GEC) dysfunction is a key driver of DKD pathogenesis. Krüppel-like factor 2 (KLF2), a shear stress-induced transcription factor, is among the highly regulated genes in early DKD. In the kidney, KLF2 expression is mostly restricted to endothelial cells, but its expression is also found in immune cell subsets. KLF2 expression is upregulated in response to increased shear stress by the activation of mechanosensory receptors but suppressed by inflammatory cytokines, both of which characterize the early diabetic kidney milieu. KLF2 expression is reduced in progressive DKD and hypertensive nephropathy in humans and mice, likely due to high glucose and inflammatory cytokines such as TNF-α. However, KLF2 expression is increased in glomerular hyperfiltration-induced shear stress without metabolic dysregulation, such as in settings of unilateral nephrectomy. Lower KLF2 expression is associated with CKD progression in patients with unilateral nephrectomy, consistent with its endoprotective role. KLF2 confers endoprotection by inhibition of inflammation, thrombotic activation, and angiogenesis, and thus KLF2 is considered a protective factor for cardiovascular disease (CVD). Based on similar mechanisms, KLF2 also exhibits renoprotection, and its reduced expression in endothelial cells worsens glomerular injury and albuminuria in settings of diabetes or unilateral nephrectomy. Thus KLF2 confers endoprotective effects in both CVD and DKD, and its activators could potentially be developed as a novel class of drugs for cardiorenal protection in diabetic patients.
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Nefropatías Diabéticas , Factores de Transcripción de Tipo Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Humanos , Animales , Células Endoteliales/metabolismo , Células Endoteliales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Riñón/metabolismo , Riñón/patologíaRESUMEN
C3 glomerulopathy (C3G) is a rare disorder marked by deposition of C3 in the glomerulus, resulting in damage to the glomerular filtration unit and presenting with features of the nephritic and nephrotic syndromes. Fundamentally, C3G is caused by dysregulation of the alternative pathway of the complement cascade, either due to genetic variants or acquired humoral factors. Despite significant advances in recent years in the understanding of the underlying mechanisms and culprit lesions that result in the development of C3G, treatment options remain severely limited, and the prognosis is often poor. Fortunately, a number of anticomplement therapies are emerging from the drug development pipeline, with several in late-stage testing in patients with C3G, and there is hope that we will soon have more targeted options for managing patients with this devastating disease. In this review, we provide an overview of C3G, as well as summarizing the evidence for current treatments and detailing the clinical trials that are currently underway.
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Complemento C3 , Humanos , Complemento C3/metabolismo , Complemento C3/genética , Complemento C3/inmunología , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Vía Alternativa del Complemento/genética , Vía Alternativa del Complemento/efectos de los fármacos , Glomerulonefritis/patología , Glomerulonefritis/metabolismo , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glomerulonefritis/terapia , Glomerulonefritis/diagnóstico , Síndrome Nefrótico/patología , Síndrome Nefrótico/genética , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/terapiaRESUMEN
The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2-/-) mice similarly observed in Ccr2-/- mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5-/- mice but not when only glomerular macrophage infiltration was inhibited in Ccr5-/- mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2-/- and Ccr2-/- mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2-/- mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.
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Quimiocina CCL2 , Glomérulos Renales , Nefritis Lúpica , Macrófagos , Receptores CCR2 , Animales , Nefritis Lúpica/patología , Nefritis Lúpica/inmunología , Nefritis Lúpica/metabolismo , Quimiocina CCL2/metabolismo , Receptores CCR2/metabolismo , Receptores CCR2/genética , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Infiltración Neutrófila , Ratones Endogámicos MRL lpr , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Femenino , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Transducción de SeñalRESUMEN
In the past few decades, the global prevalence of diabetes has provided us with a warning about future chronic complications. Diabetic nephropathy (DN) is the main cause of end-stage kidney disease. Podocytes in the glomerulus play a critical role in regulating glomerular permeability, and podocyte injury is one of the main causes of DN. Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase family that plays critical roles in intracellular signal transduction. In human patients with DN, phosphorylated ERK (pERK), the active form of ERK, is increased in the glomeruli. However, information on the expression of pERK, specifically in podocytes in DN, is limited. Meanwhile, high glucose induces ERK activation in immortalized podocyte cell lines, suggesting the involvement of podocytic ERK in DN. We performed an immunohistochemical study using Wilms' tumor-1 (WT-1) as a podocyte-specific marker to investigate whether podocytic pERK levels are increased in patients with DN. In the glomeruli of the DN group, we observed remarkable co-staining for WT-1 and pERK. In contrast, the glomeruli of the control group contained only a few pERK-positive podocytes. Statistical analyses revealed that, relative to healthy controls, patients with DN showed significantly increased pERK expression levels in cells that were positive for WT-1 (DN: 51.3 ± 13.1% vs. control: 7.3 ± 1.6%, p = 0.0158, t-test, n = 4 for each group). This suggests that ERK activation in podocytes is involved in the pathogenesis of DN.
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Nefropatías Diabéticas , Quinasas MAP Reguladas por Señal Extracelular , Podocitos , Humanos , Podocitos/metabolismo , Podocitos/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/etiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Proteínas WT1/metabolismo , Proteínas WT1/genética , Fosforilación , Activación Enzimática , Anciano , Adulto , Glomérulos Renales/patología , Glomérulos Renales/metabolismoRESUMEN
OBJECTIVE: Utilizing ultrasound radiomics, we developed a machine learning (ML) model to construct a nomogram for the non-invasive evaluation of glomerular status in diabetic kidney disease (DKD). MATERIALS AND METHODS: Patients with DKD who underwent renal biopsy were retrospectively enrolled between February 2017 and February 2023. The patients were classified into mild or moderate-severe glomerular severity based on pathological findings. All patients were randomly divided into a training (n =79) or testing cohort (n = 35). Radiomic features were extracted from ultrasound images, and a logistic regression ML algorithm was applied to construct an ultrasound radiomic model after selecting the most significant features using univariate analysis and the least absolute shrinkage and selection operator algorithm (LASSO). A clinical model was created following univariate and multivariate logistic regression analyses of the patient's clinical characteristics. Then, the clinical-radiomic model was constructed by combining rad scores and independent clinical characteristics and plotting the nomogram. The receiver operating characteristic curve (ROC) and decision curve analysis (DCA), respectively, were used to evaluate the prediction abilities of the clinical model, ultrasound-radiomics model, and clinical-radiomics model. RESULTS: A total of 114 DKD patients were included in the study, including 43 with mild glomerulopathy and 71 with moderate-severe glomerulopathy. The area under the curve (AUC) for the clinical model based on clinical features and the radiomic model based on 2D ultrasound images in the testing cohort was 0.729 and 0.761, respectively. Further, the AUC for the clinical-radiomic nomogram was constructed by combining clinical features, and the rad score was 0.850 in the testing cohort. The outcomes were better than those of both the radiomic and clinical single-model approaches. CONCLUSION: The nomogram constructed by combining ultrasound radiomics and clinical features has good performance in assessing the glomerular status of patients with DKD and will help clinicians monitor the progression of DKD.
.Asunto(s)
Nefropatías Diabéticas , Nomogramas , Ultrasonografía , Humanos , Nefropatías Diabéticas/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Ultrasonografía/métodos , Estudios Retrospectivos , Glomérulos Renales/diagnóstico por imagen , Glomérulos Renales/patología , Aprendizaje Automático , Adulto , Curva ROC , Anciano , RadiómicaRESUMEN
Glomerulomegaly and focal segmental glomerulosclerosis are histopathological hallmarks of obesity-related glomerulopathy (ORG). Podocyte injury and subsequent depletion are regarded as key processes in the development of these glomerular lesions in patients with ORG, but their impact on long-term kidney outcome is undetermined. Here, we correlated clinicopathological findings and podocyte depletion retrospectively in patients with ORG. Relative (podocyte density) and absolute (podocyte number per glomerulus) measures of podocyte depletion were estimated using model-based stereology in 46 patients with ORG. The combined endpoint of kidney outcomes was defined as a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure. Patients with lower podocyte density were predominantly male and had larger body surface area, greater proteinuria, fewer non-sclerotic glomeruli, larger glomeruli and higher single-nephron eGFR. During a median follow-up of 4.1 years, 18 (39%) patients reached endpoint. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density. However, there was no difference in kidney survival between patient groups based on podocyte number per glomerulus. Cox hazard analysis showed that podocyte density, but not podocyte number per glomerulus, was associated with the kidney outcomes after adjustment for clinicopathological confounders. Thus, our study demonstrates that a relative depletion of podocytes better predicts long-term kidney outcomes than does absolute depletion of podocytes. Hence, the findings implicate mismatch between glomerular enlargement and podocyte number as a crucial determinant of disease progression in ORG.
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Tasa de Filtración Glomerular , Obesidad , Podocitos , Humanos , Podocitos/patología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Obesidad/complicaciones , Adulto , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/etiología , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomérulos Renales/patología , Progresión de la Enfermedad , Proteinuria/etiología , Proteinuria/patología , Recuento de Células , Factores de Tiempo , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. METHODS: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. FINDINGS: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. INTERPRETATION: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. FUNDING: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.
Asunto(s)
Modelos Animales de Enfermedad , Inmunoglobulina A , Mucosa Intestinal , Glomérulos Renales , Ratones Noqueados , Animales , Ratones , Inmunoglobulina A/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Disbiosis , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/patología , Complejo 1 de Proteína Adaptadora/metabolismo , Complejo 1 de Proteína Adaptadora/genética , Transducción de Señal , Factor de Transcripción STAT3/metabolismoRESUMEN
Paraproteinemias are a group of complex diseases associated with an overproduction of a monoclonal immunoglobulin that can cause a diversity of kidney disorders and end-organ damage. In this review, we focus on paraprotein-mediated glomerular diseases. Kidney biopsy plays a crucial role in diagnosing these disorders, enabling the identification of specific histological patterns. These lesions are categorized into organized (such as amyloidosis, immunotactoid glomerulopathy, fibrillary glomerulonephritis, cryoglobulinemic glomerulonephritis, and monoclonal crystalline glomerulopathies) and nonorganized deposits (such as monoclonal Ig deposition disease and proliferative glomerulonephritis with monoclonal Ig deposits) based on the characteristics of immunofluorescence findings and the ultrastructural appearance of deposits on electron microscopy. This review aims to provide an update, highlight, and discuss clinicopathological aspects such as definition, epidemiology, clinical manifestations, mechanisms of kidney injury, histological features, and diagnostic procedures.
Asunto(s)
Glomerulonefritis , Glomérulos Renales , Paraproteinemias , Humanos , Paraproteinemias/patología , Paraproteinemias/diagnóstico , Paraproteinemias/metabolismo , Glomerulonefritis/patología , Glomerulonefritis/metabolismo , Glomerulonefritis/diagnóstico , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Paraproteínas/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Biopsia , Amiloidosis/patología , Amiloidosis/metabolismo , Amiloidosis/diagnósticoRESUMEN
Transcript analyses highlight an important contribution of natural killer (NK) cells to microvascular inflammation (MVI) in antibody-mediated rejection (ABMR), but only few immunohistologic studies have quantified their spatial distribution within graft tissue. This study included 86 kidney transplant recipients who underwent allograft biopsies for a positive donor-specific antibody (DSA) result. NK cells were visualized and quantified within glomeruli and peritubular capillaries (PTC), using immunohistochemistry for CD34 alongside CD16/T-bet double-staining. Staining results were analyzed in relation to histomorphology, microarray analysis utilizing the Molecular Microscope Diagnostic System, functional NK cell genetics, and clinical outcomes. The number of NK cells in glomeruli per mm2 glomerular area (NKglom) and PTC per mm2 cortical area (NKPTC) was substantially higher in biopsies with ABMR compared to those without rejection, and correlated with MVI scores (NKglom Spearman's correlation coefficient [SCC] = 0.55, p < 0.001, NKPTC 0.69, p < 0.001). In parallel, NK cell counts correlated with molecular classifiers reflecting ABMR activity (ABMRprob: NKglom 0.59, NKPTC 0.75) and showed a trend towards higher levels in association with high functional FCGR3A and KLRC2 gene variants. Only NKPTC showed a marginally significant association with allograft function and survival. Our immunohistochemical results support the abundance of NK cells in DSA-positive ABMR.