Neutrophil extracellular traps potentiate effector T cells via endothelial senescence in uveitis

JCI Insight, Journal Year: 2025, Volume and Issue: 10(2)

Published: Jan. 22, 2025

Autoimmune uveitis (AU) is a sight-threatening ocular autoimmune disorder that often manifests as retinal vasculitis. Increased neutrophil infiltration around vessels has been reported during the progression of AU, while how they function not fully recognized. Neutrophil extracellular traps (NETs), produced by activated neutrophils, have suggested to be detrimental in diseases. Here, we found NETs were elevated patients with active and this was verified an experimental AU (EAU) mouse model. Depletion neutrophils or degradation deoxyribonuclease-I (DNase I) could decrease CD4+ effector T cell (Teff) retina spleen alleviate EAU. Moreover, expression adhesion molecules, selectin, antigen-presenting molecules EAU microvascular endothelial cells (RMECs) cocultured NETs. The stimulated RMECs further facilitated adhesion, activation, differentiation into Teffs. Mechanistically, trigger RMEC activation hastening senescence through cyclic GMP-AMP synthase (cGAS)/stimulator interferon genes (STING) pathway. Slowing down inhibiting cGAS/STING pathway reduces cells. These results suggest deleterious role AU. Targeting would offer effective therapeutic method.

Language: Английский

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Membranous nephropathy: Systems biology-based novel mechanism and traditional Chinese medicine therapy

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 13, 2022

Membranous nephropathy (MN) is a renal-limited non-inflammatory autoimmune disease in the glomerulus, which second or third main cause of end-stage kidney diseases patients with primary glomerulonephritis. Substantial achievements have increased our understanding aetiology and pathogenesis murine human MN. The identification nephritogenic autoantibodies against neutral endopeptidase, phospholipase A 2 receptor (PLA R) thrombospondin type-1 domain-containing 7A (THSD7A) antigens provide more specific concept-driven intervention strategies for treatments by B cell-targeting monoclonal antibodies to inhibit antibody production antibody-antigen immune complex deposition. Furthermore, additional specificities been discovered, but their pathogenic effects are uncertain. Although anti-PLA R anti-THSD7A as diagnostic marker widely used MN patients, many questions including response development, antigenic epitopes, podocyte damage signalling pathways remain unresolved. This review describes current available evidence regarding both established novel molecular mechanisms based on systems biology approaches (gut microbiota, long non-coding RNAs, metabolite biomarkers DNA methylation) MN, an emphasis clinical findings. further summarizes applications traditional Chinese medicines such Tripterygium wilfordii Astragalus membranaceus treatment. Lastly, this considers how antibodies/antigens unresolved future challenges reveal

Language: Английский

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Recent Advances in Clinical Diagnosis and Pharmacotherapy Options of Membranous Nephropathy

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: May 26, 2022

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome among adults, which leading glomerular disease that recurs after kidney transplantation. Treatment for MN remained controversial and challenging, partly owing to absence sensitive specific biomarkers effective therapy prediction diagnosis activity. starts with formation deposition circulating immune complexes on outer area in basement membrane, complement activation. The identification autoantibodies against phospholipase A2 receptor (PLA2R) thrombospondin type-1 domain-containing protein 7A (THSD7A) antigens illuminated a distinct pathophysiological rationale treatments. Nowadays, detection serum anti-PLA2R antibodies deposited PLA2R antigen can be routinely applied MN. Anti-PLA2R exhibited much high specificity sensitivity. Measurement complex allows PLA2R-associated patients renal biopsies. In review, we critically summarized newer including THSD7A tests novel promising therapies by using traditional Chinese medicines such as Astragalus membranaceus, Tripterygium wilfordii, Astragaloside IV treatment patients. We also described unresolved questions future challenges reveal treatments These unprecedented breakthroughs were quickly translated clinical management. Considerable advances methods played critical role monitoring treatment.

Language: Английский

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Screening potential diagnostic biomarkers for PLA2R‑associated idiopathic membranous nephropathy by WGCNA analysis and LASSO algorithm

Renal Failure, Journal Year: 2025, Volume and Issue: 47(1)

Published: Jan. 13, 2025

Adult nephrotic syndrome is primarily caused by membranous nephropathy (MN), with idiopathic (IMN) being a prominent subtype. The onset of phospholipase A2 receptor (PLA2R1)-associated IMN critically linked to M-type PLA2R1 exposure, yet the mechanism underlying glomerular injury remains unclear. In this study, datasets (GSE115857, GSE200828) were retrieved from GEO. Differential gene expression was analyzed using 'limma' R package. WGCNA filtered PLA2R-related modules and intersected genes. LASSO regression, evaluated ROC analysis, identified characteristic Binomial logistic regression assessed their association IMN. Validation performed in GSE133288 dataset. IHC qRT-PCR detected PLA2R-positive patients. This study elevated PLA2R patients among 117 DEGs. PPI analysis suggested enrichment Golgi membranes, co-regulation, glucocorticoid responsiveness, implicating PPAR pathway KEGG. revealed 440-gene brown module associated IMN-PLA2R, ECM1, SLC19A2, RASD1, FOSB, KDELR3, ZFP36, ELF4 highlighted as diagnostic markers analysis. Clinical validation confirmed ECM1 upregulation increased risk, while FOSB decreased it. positively correlated PLA2R, whereas negatively correlated. demonstrated consistent patterns tissues, podocyte exposure serum reducing viability increasing apoptosis. Functional studies, prompted RASD1 downregulation, enhanced cell activity reduced apoptosis upon overexpression compared Serum + Ov-NC control. Collectively, for IMN, offering novel therapeutic targets treatment

Language: Английский

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Effectiveness of a Novel PLA2R1 Knock‐In Rat Model in Repairing Renal Function Damage

Journal of Biochemical and Molecular Toxicology, Journal Year: 2025, Volume and Issue: 39(1)

Published: Jan. 1, 2025

Phospholipase A2 receptor 1 (PLA2R1) exists in many animals and plays an important role membranous nephropathy. In this study, we aimed to evaluate a PLA2R1 knock-in rat model with repaired kidney function study the molecular mechanisms of We constructed knockout [PLA2R1(-)] knock [PLA2R1(+)] rats. Consistent complement C3 IgA expression was confirmed through colocalization studies. Urinary biochemical indicators were performed using Automatic Biochemistry Analyzer. The C3, IgG, Nephrin detected by immunofluorescence assay. levels IgA, western blot. differential proteins (DEPs) between control PLA2R1(+) models liquid chromatography tandem mass spectrometry. PLA2R1(-) showed proteinuria, aggregation, IgG deposition glomerulus. Comparing model, glomerulus did not completely disappear, weakened. Moreover, absolute value urinary protein much lower than some humanized gene fragments functions. Humanized PLA2R1-insertion rats can repair part renal reduce which will help studying nephropathy, as well entire nephropathy-related system activation signaling pathway.

Language: Английский

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Membranous Nephropathy Target Antigens Display Podocyte-Specific and Non-Specific Expression in Healthy Kidneys

Genes, Journal Year: 2025, Volume and Issue: 16(3), P. 241 - 241

Published: Feb. 20, 2025

Background/Objectives: Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their expression has not thoroughly studied. Methods: We screened CZ CELLxGene single-cell RNA (scRNA) sequence datasets for those of adult, fetal, mouse kidneys analyzed the above MNTAgs’ expression. Results: In adult kidneys, most MNTAgs are present in podocytes, except PCSK6 NCAM1. PLA2R1 is expressed significantly more than other podocytes a major marker, consistent with as dominant MNTAg. Additionally, top-upregulated gene chronic kidney disease, acute injury, diabetic nephropathy, indicating its general role causing injury. NDNF display podocyte-enriched along elevated chromatin accessibility suggesting transcription initiation contributing to preference podocytes. fetal kidney, While weakly SEMA3B abundantly immature mature supporting childhood Thsd7a only MNTAg prominent level podocyte-specific Conclusions: Most adults during renal development. adults, highly enriched upregulated multiple diseases accompanied by proteinuria. specifically at an level.

Language: Английский

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Family study of bipolar disorder with comorbid anxiety disorder points to THSD7A with possible role of parent‐of‐origin effect

Psychiatry and Clinical Neurosciences Reports, Journal Year: 2025, Volume and Issue: 4(1)

Published: Feb. 19, 2025

The aim of this study was to provide new insights into the genetics bipolar disorder (BD) by analyzing BD comorbid with anxiety disorders. Structured interviews were conducted patients and their parents. Cases classified those spectrum (AS) without. family history AS assessed. Focusing on parent-of-origin effects genomic imprinting from results, imprinted genes tested single nucleotide polymorphisms (SNPs) in identified investigated for an association transmission disequilibrium test (TDT) using published whole-exome sequencing data. incidence among all analyzed 39.6%. Patients whose fathers had or mood disorders exhibited a significantly higher rate AS. Among known genes, two associated BD: THSD7A CACNA1C. By pruning SNPs, six variants exons four CACNA1C included analysis. these, one variant THSD7A, rs2074603, showed over-transmission parents BD. Furthermore, it nominally significant only when TDT performed separately mothers. may play role effects. Further research is necessary explore mechanisms which Clinical Trial Registration: N/A.

Language: Английский

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Role of PLA2R domain antibodies and epitope spreading in risk stratification and prediction of proteinuria remission in primary membranous nephropathy

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 26, 2025

Language: Английский

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An exceptional presentation of nephrotic syndrome: bilateral massive pulmonary embolism

Blood Coagulation & Fibrinolysis, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Venous thromboembolism (TE) and arterial TE are rare in children, but can cause severe morbidity mortality. The incidence of is 8.6-57 per 100 000 among hospitalized children 0.14-0.9 the general pediatric population. risk increased nephrotic syndrome (NS) patients. thromboembolic complications NS patients approximately 3%. Herein we report a patient that presented with massive bilateral pulmonary embolism (PE) whom underlying condition was NS. At onset clinical course findings were attributed to heart failure and, therefore, diagnosis treatment delayed. Based on case, think clinicians should consider PE when hypoalbuminemia, diffuse edema, proteinuria present, timely initiation concomitant administration yield positive results. We further diagnosed have generalized be considered for started without delay concomitantly order achieve result.

Language: Английский

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Clinical and morphological features of glomerulopathies and their prognostic significance in malignant tumors of various locations

Kazan medical journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

This literature review analyzes the results of international studies conducted over past five years, focusing on glomerulopathies associated with malignant neoplasms various locations. The aim this is to conduct a comparative analysis histological and immunohistochemical features morphological characteristics in across locations, as well determine specificity identified features. research data were retrieved using Scopus, PubMed, Cochrane Library databases, limited publications from 2019 2024. study provided detailed changes glomerular apparatus carcinomas evaluated described Special attention was given pathogenetic mechanisms hypothesized explain development different A topic demonstrates that understanding contributes improvement diagnostic methods for such conditions. importance field cannot be overstated, it may provide new insights developing innovative approaches aimed at enhancing prognosis quality life patients oncological diseases. Malignant tumor cells can express substances, including proteins, which lead glomerulopathy. Analysis helps identify presence or absence link between glomerulopathy, enabling adjustments patient’s treatment plan. Additionally, part focuses exploring potential pathophysiological underlying neoplasms, facilitates more accurate diagnosis distinguishes specific nonspecific characteristics. Thus, provides an emphasizing interdisciplinary approach diagnosing condition one clinical manifestations tumors.

Language: Английский

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