Kidney international最新文献

{"title":"Genetic screens of imaging-derived kidney volumes identify genes linked to kidney function.","authors":"Sara Monteiro-Martins,Yong Li,Oleg Borisov,Atlas Khan,Wilfried Reichardt,Stefan Haug,Elias Kellner,Martin Buechert,Elisabeth Ott,Maximilian Frederik Russe,Fabian Bamberg,Krzysztof Kiryluk,Peggy Sekula,Marco Reisert,Anna Köttgen","doi":"10.1016/j.kint.2025.08.038","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.038","url":null,"abstract":"INTRODUCTIONChronic kidney disease (CKD) is defined as sustained abnormalities in kidney function or structure. Genetic studies of CKD have largely focused on kidney function markers such as estimated glomerular filtration rate (eGFR). We hypothesized that genome-wide association studies (GWAS) of magnetic resonance imaging (MRI)-based kidney sub-volumes could provide insights into CKD risk genes complementary to the study of eGFR.METHODSTotal kidney volume (TKV) and sub-volumes for cortex, medulla, and sinus were derived from abdominal MRIs of 38,816 United Kingdom Biobank participants of European ancestry using a trained convolutional neural network. GWAS was performed for body surface area-normalized kidney volumes and eGFR for comparison. Potentially causal genes at each locus were prioritized using a developed annotation pipeline. We assessed locus overlap between volumes, biomarker-based kidney function, and clinical traits using colocalization analyses. Annotated genes were further characterized through enrichment analyses, molecular and clinical annotations, including a screen for rare, putative loss-of-function variants.RESULTSGWAS for 9,803,932 common genetic variants identified 34 significant loci for TKV, 24 for medulla, 26 for cortex, and 71 for sinus, compared to 32 for eGFR. Prioritized genes for cortex and medulla volumes showed corresponding tissue-specific expression and were enriched for kidney development- and hypoxia-related pathways. Genetic effect sizes of significant index single nucleotide polymorphisms for TKV, cortex, and medulla volumes correlated positively with those for eGFR. Some loci such as PKHD1 and BICC1 were strongly associated with kidney volumes but not eGFR. Integration with disease information revealed that rare, putative loss-of-function variants in BICC1, and common variants with regulatory potential, are associated with increased risk for CKD and dialysis, which was not identified in a previous GWAS of eGFR CONCLUSIONS: Our investigation shows that genetic findings of kidney structure can complement kidney function studies and reveal previously unrecognized CKD risk genes in the population.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"86 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inactivation of Pkd2 in adult mice results in delayed cyst formation and identifies sex as a major modifier of disease severity.","authors":"Patricia Outeda,Perry Summers,Denis Basquin,Ruizhen Xu,Jessica Hunt,Luis F Menezes,Terry Watnick","doi":"10.1016/j.kint.2025.08.039","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.039","url":null,"abstract":"INTRODUCTIONAutosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 and is the most common single-gene disorder resulting in kidney failure. Since deletion of either Pkd1 or Pkd2 in mice is embryonically lethal, conditional alleles have become indispensable tools for studying the pathobiology of ADPKD and for preclinical testing. The rapidity of cyst formation in Pkd1 conditional mice depends on the timing of gene inactivation, but this has never been systematically studied for Pkd2. Here, we characterize the kinetics of cystogenesis in a Pkd2 conditional mouse model and identify associated alterations in gene expression.METHODSUsing a conditional mouse model, we inactivated Pkd2 at different postnatal stages and characterized the severity of cyst formation. Additionally, we performed RNA-sequencing analysis to identify gene expression changes associated with Pkd2 loss in males and females.RESULTSThere is a similar developmental switch in Pkd2 conditional mice with delayed cyst formation after Pkd2 inactivation at or beyond postnatal day 14. Like Pkd1 models, cystogenesis is associated with differential expression of genes involved in metabolism, cell proliferation, and immune response. We confirm that sex is a key modifier of ADPKD progression with differences in disease severity occurring in the context of significant transcriptional differences between males and females that are independent of the Pkd2 genotype.CONCLUSIONSPkd2 conditional mice are a useful model for understanding ADPKD pathogenesis and for testing therapeutics. Our data highlight the importance of sex as a biological variable that should be considered in any study design using orthologous mouse models with late Pkd2 inactivation.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"6 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A randomized controlled trial evaluated the effect of pravastatin on kidney disease outcomes in adult patients with early-stage autosomal dominant polycystic kidney disease.","authors":"Berenice Y Gitomer,Anna Ostrow,Wei Wang,Diana George,Erin Coleman,Kristen L Nowak,Melissa A Cadnapaphornchai,Nayana U Patel,Cortney Steele,Anna Jovanovich,Jelena Klawitter,Beverly Farmer,Zhiying You,Michel Chonchol","doi":"10.1016/j.kint.2025.08.037","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.037","url":null,"abstract":"INTRODUCTIONWhether treatment with pravastatin mitigates kidney dysfunction in adult patients with early autosomal dominant polycystic kidney disease (ADPKD) is unknown. To answer this, we performed a prospective, randomized, controlled, double-blind clinical trial in 150 patients (52 males and 98 females; 25-60 years) with ADPKD, and an estimated glomerular filtration rate (eGFR) of 60 ml/min or more per 1.73m2.METHODSPatients were randomly assigned to receive 40 mg of pravastatin or a placebo for two years. The primary outcome was the annual change in height-adjusted total kidney volume (HtTKV). Secondary outcomes were the annual change in kidney blood flow by magnetic resonance angiography and the annual change in measured GFR (mGFR).RESULTSAmong the participants who underwent randomization, the annual rate of increase in HtTKV median (interquartile range) was: 3.1% (1.4, 6.8) in the placebo and the pravastatin 4.3% (3.0, 6.6) group. The annual rate of decline in kidney blood flow (ml/min per 1.73m2) was -32.7 (-62.1, -0.8) in placebo vs. -15.1 (-50.7, 14.4) in the pravastatin group. The median change in mGFR (ml/min per 1.73m2) -2.3 (-5.1, 1.6) for placebo and -1.4 (-6.4, 2.0) for the pravastatin group. Overall, no parameter differed significantly between treatment groups. There was a similar trend in patients with faster disease progression (Mayo Imaging Class 1C, D, and E).CONCLUSIONSAmong adult patients with ADPKD and preserved kidney function, pravastatin did not slow the increase in HtTKV and had no effect on slowing the decline in kidney blood flow and kidney function compared to placebo.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"79 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hierarchical clustering uncovered disease patterns and further untangled complexities in immune complex-mediated idiopathic MPGN and C3 glomerulopathy.","authors":"Ariela Benigni,Erica Daina,Henry Löffler-Wirth,Rossella Piras,Miriam Rigoldi,Maria Schmidt,Camillo Carrara,Roberta Donadelli,Zahra Imanifard,Caterina Mele,Marta Alberti,Maddalena Marasà,Carolina Martinatto,Elena Bresin,Sara Gamba Res,Lisa Quadri,Giliane Nanchen,Marina Vivarelli,Francesco Emma,Gaetano La Manna,Enrico Vidal,Andrea Pasini,Andrea Ranghino,Gabriele Donati,Enrico Verrina,Andrea Angeletti,Giuliano Brunori,Mario Giordano,Federico Alberici,Umberto Maggiore,Gabriele Malgieri,Giuseppe Remuzzi,Matteo Breno,Marina Noris, ","doi":"10.1016/j.kint.2025.08.035","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.035","url":null,"abstract":"INTRODUCTIONMembranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate.METHODSHere, we applied hierarchical clustering to a much larger cohort of patients with C3G/ICMPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable.RESULTSFive clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches.CONCLUSIONOur proposed strategy may possibly guide anti-complement treatment.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"13 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity in the relationships between albuminuria and glomerular structure in type 1 and type 2 diabetes.","authors":"Behzad Najafian,Maria Luiza Caramori,Michele Dalla Vestra,Alois Saller,Mehrdad Noruzinia,Michael Mauer,Paola Fioretto","doi":"10.1016/j.kint.2025.08.034","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.034","url":null,"abstract":"INTRODUCTIONKidney structural-functional relationship studies have been critical in understanding diabetic kidney disease (DKD) evolution. However, most such studies were performed in persons with type 1 diabetes, where diabetic glomerular lesions are strongly associated with albumin excretion rate (AER). Here, we compare DKD structural-functional relationships in type 1 and type 2 diabetes.METHODSTo better understand the evolution of DKD in type 2 diabetes, analyses of glomerular structure/albuminuria relationships were performed in 133 research volunteers with type 2 and 161 with type 1 diabetes matched for AER compared to 95 living donor kidney biopsies as controls.RESULTSMorphometric measures of DKD glomerular lesions were more advanced and showed stronger relationships with AER in persons with type 1 vs type 2 diabetes. K-means cluster analysis based on distance from a structural-functional relationship model derived from data of research participants with type 1 diabetes yielded two clusters: 74% of participants with type 2 diabetes were in Cluster 1, which also included most participants with type 1 diabetes, while 26% of participants with type 2 diabetes were in Cluster 2 and showed greater AER than predicted by their DKD glomerular lesions based on the model. Among those with type 2 diabetes, despite excessive AER in Cluster 2, DKD glomerular lesions and podocyte structural parameters were similar between the two clusters. However, adjusted for AER, individuals with type 2 diabetes in Cluster 1 had more severe DKD lesions and approximately four-fold greater rates of glomerular filtration rate decline over nine to ten years follow up than those in Cluster 2.CONCLUSIONSKidney structural-functional relationships are heterogeneous in individuals with type 2 diabetes, and this heterogeneity is linked to glomerular filtration rate loss over time. Our investigation calls for further studies to better understand factors involved in this heterogeneity.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"56 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mono-allelic pathogenic variants in JAG1 cause Autosomal Dominant Tubulo-interstitial Kidney Disease (ADTKD-JAG1).","authors":"Lucie Menguy,Laurent Hudier,Mohamad Zaidan,Bertrand Knebelmann,John A Sayer,Juliana Arcila Galvis,Christelle Arondel,Aurélie Hummel,Guillaume Dorval,Vincent Morinière,Landrine Fula-Pitu,Chiara Guerrera,David Buob,Maud Rabeyrin,Pierre Marijon,Nolwen Jean-Marcais,Chloé Fournier,Jean-Paul Duong Van Huyen,Corinne Antignac,Sophie Saunier,Laurence Heidet","doi":"10.1016/j.kint.2025.08.033","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.033","url":null,"abstract":"INTRODUCTIONAutosomal dominant tubulointerstitial kidney disease (ADTKD) is a common monogenic kidney disease leading to kidney failure usually during mid adulthood. It is due to pathogenic variants in at least five genes. However, despite thorough screening of UMOD, MUC1, REN, HNF1B and SEC61A1, 25 to 50% of families remain without molecular diagnosis.METHODSHere, we investigated a cohort of 203 families with ADTK, as well as sporadic cases of kidney disease of unknown etiology and cases of chronic kidney disease stage 5 from the Genomics England 100,000 genomes project. Expression of JAG1 in kidney and/or urinary epithelial cell (UREC) lines from patients carrying a pathogenic JAG1 variant associated with isolated ADTKD was studied using immunolabelling, Western blotting, targeted RNA-seq and quantitative RT-PCR. Endoplasmic reticulum (ER) stress was tested by analyzing ER protein BiP expression levels in URECs.RESULTSA pathogenic or likely pathogenic variant in JAG1, the gene associated with Alagille syndrome, was identified in three large families with unsolved ADTKD, and additional rare variants were identified in sporadic cases. In two of the families, the diagnosis of Alagille syndrome was further established in one infant in the fourth or fifth generation, however none of the 23 adult patients affected with isolated kidney failure (and tubulointerstitial nephritis in individuals with available kidney biopsy) had overt sign of liver, bile duct, heart, eye, or skeletal defect. JAG1 expression studies as well ER stress analysis suggests that, despite a noteworthy expression of the JAG1 mutated RNAs, the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.CONCLUSIONSJAG1 pathogenic variants can be associated with isolated tubulointerstitial nephropathy which, according to the KDIGO guidelines, should be classified as ADTKD-JAG1 when JAG1 variants lead to isolated chronic kidney disease that fulfils the criteria for ADTKD.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"15 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient anti-PLA2R1 autoantibodies cause membranous nephropathy in human PLA2R1 transgenic mice.","authors":"Gunther Zahner,Silke Dehde,Larissa Seifert,Ming Huang,Oliver Kretz,Tobias B Huber,Nicola M Tomas","doi":"10.1016/j.kint.2025.08.026","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.026","url":null,"abstract":"INTRODUCTIONThe discovery of anti-phospholipase A2 receptor 1 (PLA2R1) autoantibodies in patients with membranous nephropathy (MN) has led to a paradigm change in diagnosis, monitoring, risk prediction, and therapy of this autoimmune disease. However, there is only limited data on the pathogenicity of these autoantibodies.METHODSWe purified the IgG from sera of patients with PLA2R1-associated MN and injected it into Rag2-deficient mice (mice lacking functional adaptive immunity) expressing human PLA2R1 in their podocytes. The IgG-depleted serum from the same patients and IgG purified from healthy individuals served as controls.RESULTSTwo weeks after transfer, mice receiving anti-PLA2R1 IgG (largely IgG4), but not IgG-depleted serum or control IgG, developed proteinuria and showed granular deposition of human IgG and complement components of both the classical and alternative pathways in glomeruli by immunofluorescence and podocyte foot process effacement and subepithelial electron dense deposits in electron microscopy. There was no mouse IgG deposited. The IgG eluted from glomeruli of anti-PLA2R1 IgG-injected mice exclusively recognized PLA2R1.CONCLUSIONSOur findings provide evidence for a direct pathogenic role of anti-PLA2R1 autoantibodies, supporting the development of treatments aiming at the reduction of anti-PLA2R1 autoantibody levels.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"101 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changing paradigms of studies in kidney diseases.","authors":"Adeera Levin,Allison Jaure,Dustin J Little,Jane Schell,Jennifer S Lees,Kai-Uwe Eckardt,Kevin Weinfurt,Matthias Rose,Meg J Jardine,Morgan E Grams,Patrick Schloemer,Rathika Krishnasamy,Smeeta Sinha,Fergus J Caskey,Masaomi Nangaku,David C Wheeler,Louise Oni,Jaquelyne T Hughes,Bill Wang,Charles Cook,Duane Sunwold,Jocelyn Jones,Kate Chong,Thomas Ng,Jo-Ann Donner,Sandrine Damster,Charu Malik,Hiddo J L Heerspink, ","doi":"10.1016/j.kint.2025.09.016","DOIUrl":"https://doi.org/10.1016/j.kint.2025.09.016","url":null,"abstract":"Recognizing kidney disease as a major global health issue, the International Society of Nephrology (ISN) convened a two-day international, multi-stakeholder meeting to develop a roadmap for advancing clinical research in nephrology. The meeting focused on promoting the use of patient-reported outcome measures (PROMs), moving beyond single biomarker targets, adopting innovative trial designs, and incorporating hierarchical composite endpoints. Participants included clinicians, trialists, regulators, patient partners, and industry experts invited from all ISN regions. Discussions emphasized the importance of inclusive trial design, validation of PROMs, predictive enrichment strategies, and broader trial accessibility across resource settings. Key recommendations included enhancing diversity in trial populations, avoiding overreliance on isolated biomarkers, adopting novel study designs, strengthening public-private partnerships, and validating composite endpoints. A coordinated effort was deemed essential to implement these strategies in both research and practice, ensuring sustainable progress and reducing the global burden of kidney disease.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"6 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development.","authors":"Hiroki Okushima,Kazunori Inoue,Atsuhiro Imai,Ayumi Matsumoto,Natsune Tamai,Masataka Kunii,Nobuhisa Iriuchijima,Rüdiger Adam,Yusriya Al Rawahi,Siham Al Sinani,Takeshi Yamamoto,Masayuki Mizui,Akihiro Harada,Motoko Yanagita,Yoshitaka Isaka,Isao Matsui","doi":"10.1016/j.kint.2025.08.027","DOIUrl":"https://doi.org/10.1016/j.kint.2025.08.027","url":null,"abstract":"INTRODUCTIONEpithelial cell polarity is crucial for the proper functioning of various organs, including the kidneys. Syntaxin 3, a key molecule in membrane-vesicle fusion, is localized in the apical membrane of proximal tubule epithelial cells (PTECs). Although in vitro studies using the other type of epithelial cells besides PTECs have shown the role of syntaxin 3 in regulating apical membrane integrity, its function in epithelial cells in vivo, particularly in PTECs, remains undefined.METHODSWe analyzed the renal phenotypes of a newly generated PTEC-specific Stx3 knockout mice (Stx3-cKO) and examined urine samples from patients with microvillus inclusion disease (MVID) carrying STX3 mutations.RESULTSStx3-cKO mice exhibited features of Fanconi syndrome, including increased urinary excretion of phosphorus, glucose, amino acids, and low-molecular-weight proteins. Patients with MVID showed similar urinary abnormalities. The mice exhibited brush border atrophy and vesicle transport stagnation, as evidenced by electron microscopy, and increased subapical localization of trafficking markers, Rab11 and vesicle-associated membrane protein 8. Key transporters and receptors including sodium-dependent phosphate cotransporter type 2a, sodium-glucose cotransporter 2, a protein related to the neutral and basic amino acid transport protein rBAT, and megalin showed mislocalization and/or altered expression. Syntaxin 3 deficiency disrupted the apical expression of ezrin, a crucial protein that links the actin cytoskeleton to the plasma membrane. Both receptor-mediated and fluid-phase endocytosis were impaired in Stx3-cKO mice.CONCLUSIONSOur results highlight the critical role of syntaxin 3 in maintaining PTEC function and apical polarity, providing new insights into the kidney manifestations of MVID and the molecular mechanisms underlying Fanconi syndrome.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"24 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages mediate acute kidney allograft rejection via a toll-like receptor 4-dependent mechanism.","authors":"Qixia Shen,Tingting Zhu,Sijing Yan,Yucheng Wang,Cuili Wang,Lisha Teng,Shi Feng,Xiao-Ru Huang,Sydney C W Tang,Hongfeng Huang,Song Rong,Xiujin Shen,Lihui Qu,Zhouji Shen,Enyin Lai,Hui-Yao Lan,Jianghua Chen,Hong Jiang","doi":"10.1016/j.kint.2025.09.014","DOIUrl":"https://doi.org/10.1016/j.kint.2025.09.014","url":null,"abstract":"INTRODUCTIONMacrophages play an important role in acute renal allograft rejection (RAR). Here we report that macrophages mediate acute RAR via a toll-like receptor 4 (TLR4)-dependent mechanism.METHODSAcute RAR was induced in myeloid cell-specific TLR4 knockout mice. Rejection severity was assessed by Banff scores, kidney immune cell infiltration/activation, and kidney function. Mechanisms were investigated using single cell RNA sequencing (scRNA-seq) and pharmacological hypoxia-inducible factor (HIF)1α inhibition. Immune profiling evaluated macrophage polarization, antigen presentation and T cell subsets.RESULTSDisruption of myeloid TLR4 largely suppressed acute RAR, evidenced by lower Banff scores, inhibited kidney immune cell infiltration and activation, and preserved kidney function. scRNA-seq identified HIF1Α as a key downstream target of myeloid TLR4. Importantly, both genetic TLR4 ablation and pharmacological HIF1α inhibition attenuated acute RAR via reducing proinflammatory macrophages (F4/80+ iNOS+ and F4/80+ HIF1α+), suppressing antigen presenting by F4/80+MHCII+ macrophages and modulating T cell immunity by suppressing CD8+ T cells and Th1 cells, while expanding regulatory T cell and Th2 populations. Notably, targeting TLR4/HIF1α signaling also ameliorated fibrosis in long-term allograft rejection.CONCLUSIONSMacrophages mediate acute RAR via a TLR4/HIF1α-dependent mechanism. Targeting TLR4/HIF1α signaling may be a novel therapeutic strategy for acute RAR, with additional benefits mitigating chronic allograft injury.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"9 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}