The Journal of Clinical Investigation最新文献

{"title":"Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.","authors":"Natalia Dominik,Stephanie Efthymiou,Christopher J Record,Xinyu Miao,Renee Q Lin,Jevin M Parmar,Annarita Scardamaglia,Reza Maroofian,Simon A Lowe,Gabriel N Aughey,Abigail D Wilson,Riccardo Curro,Ricardo P Schnekenberg,Shahryar Alavi,Leif Leclaire,Yi He,Kristina Zhelcheska,Yohanns Bellaiche,Isabelle Gaugué,Mariola Skorupinska,Liedewei Van de Vondel,Sahar I Da'as,Valentina Turchetti,Serdal Güngör,Gavin V Monahan,Ehsan Ghayoor Karimiani,Yalda Jamshidi,Phillipa J Lamont,Camila Armirola-Ricaurte,Haluk Topaloglu,Albena Jordanova,Mashaya Zaman,Selina H Banu,Wilson Marques,Pedro J Tomaselli,Busra Aynekin,Ali Cansu,Huseyin Per,Ayten Güleç,Javeria Raza Alvi,Tipu Sultan,Arif Khan,Giovanni Zifarelli,Shahnaz Ibrahim,Grazia M S Mancini,M M Motazacker,Esther Brusse,Vincenzo Lupo,Teresa Sevilla,A Nazli Başak,Seyma Tekgul,Robin J Palvadeau,Jonathan Baets,Yesim Parman,Arman Çakar,Rita Horvath,Tobias B Haack,Jan-Hendrik Stahl,Kathrin Grundmann-Hauser,Joohyun Park,Stephan Zuchner,Nigel G Laing,Lindsay A Wilson,Alexander M Rossor,James Polke,Fernanda Barbosa Figueiredo,André Pessoa,Fernando Kok,Antônio Rodrigues Coimbra-Neto,Marcondes C Franca,Gianina Ravenscroft,Sherifa A Hamed,Wendy K Chung,Alan M Pittman,Daniel P Osborn,Michael Hanna,Andrea Cortese,Mary M Reilly,James Ec Jepson,Nathalie Lamarche-Vane,Henry Houlden","doi":"10.1172/jci184474","DOIUrl":"https://doi.org/10.1172/jci184474","url":null,"abstract":"Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Here, we identify 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Combined in vitro and in vivo studies reveal that human ARHGAP19, and conserved ARHGAP19 orthologs in Drosophila and Zebrafish, influence motoneuron morphology and promote locomotor capacity. Transcriptomic studies further demonstrate that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a loss-of-function mechanism.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulated thyroid hormone synthesis machinery drives thyrocyte cell death independent of ER stress.","authors":"Crystal Young,Xiaohan Zhang,Xiaofan Wang,Aaron P Kellogg,Kevin Pena,August Z Cumming,Xiao-Hui Liao,Dennis Larkin,Hao Zhang,Emma Mastroianni,Helmut Grasberger,Samuel Refetoff,Peter Arvan","doi":"10.1172/jci187044","DOIUrl":"https://doi.org/10.1172/jci187044","url":null,"abstract":"It is now recognized that patients and animal models expressing genetically-encoded misfolded mutant thyroglobulin (TG, the protein precursor for thyroid hormone synthesis) exhibit dramatic swelling of the endoplasmic reticulum (ER) with ER stress and cell death in thyrocytes - seen both in homozygotes (with severe hypothyroidism) and heterozygotes (with subclinical hypothyroidism). The thyrocyte death phenotype is exacerbated upon thyroidal stimulation (by thyrotropin, TSH), as cell death is inhibited upon treatment with exogenous thyroxine. TSH stimulation might contribute to cytotoxicity by promoting ER stress, or by an independent mechanism. Here we've engineered knockout mice completely lacking Tg expression. Like other animals/patients with mutant TG, these animals rapidly develop severe goitrous hypothyroidism; however, thyroidal ER stress is exceedingly low - lower even than that seen in wildtype mice. Nevertheless, mice lacking TG exhibit abundant thyroid cell death, which depends upon renegade thyroidal iodination - it is completely suppressed in a genetic model lacking effective iodination, or in Tg-KO mice treated with propylthiouracil (iodination inhibitor), or iodide deficiency. Thyrocytes in culture are killed not in the presence of H2O2 alone, but rather upon peroxidase-mediated iodination, with cell death blocked by propylthiouracil. Thus, in the thyroid gland bearing Tg mutation(s), TSH-stimulated iodination activity triggers thyroid cell death.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney-specific claudin-2 deficiency leads to medullary nephrocalcinosis in mice.","authors":"Christine V Behm,Duuamene Nyimanu,Ony Araujo Galdino,Sadhana Kanoo,Young Chul Kim,Natalia Lopez,Helen Goodluck,Peter S Rowe,Andrew P Evan,André J Sommer,Matthew N Barr,Tracy Punshon,Volker Vallon,Brian P Jackson,James C Williams,Alan Sl Yu","doi":"10.1172/jci197807","DOIUrl":"https://doi.org/10.1172/jci197807","url":null,"abstract":"Deposits of hydroxyapatite called Randall's plaques are found in the renal papilla of calcium oxalate kidney stone formers and likely serve as the nidus for stone formation, but their pathogenesis is unknown. Claudin-2 is a paracellular ion channel that mediates calcium reabsorption in the renal proximal tubule. To investigate the role of renal claudin-2, we generated kidney tubule-specific claudin-2 conditional knockout mice (KS-Cldn2 KO). KS-Cldn2 KO mice exhibited transient hypercalciuria in early life. Normalization of urine calcium was accompanied by a compensatory increase in expression and function of renal tubule calcium transporters, including in the thick ascending limb. Despite normocalciuria, KS-Cldn2 KO mice developed papillary hydroxyapatite deposits, beginning at 6 months of age, that resembled Randall's plaques and tubule plugs. Bulk chemical tissue analysis and laser ablation-inductively coupled plasma mass spectrometry revealed a gradient of intrarenal calcium concentration along the corticomedullary axis in normal mice, that was accentuated in KS-Cldn2 KO mice. Our findings provide evidence for the \"vas washdown\" hypothesis for Randall's plaque formation, and identify the corticomedullary calcium gradient as a target for therapies to prevent kidney stone disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation in myocardial ischemia/reperfusion injury.","authors":"Xiaoqi Wang,Xiangyu Yan,Ge Mang,Yujia Chen,Shuang Liu,Jiayu Sui,Zhonghua Tong,Penghe Wang,Jingxuan Cui,Qiannan Yang,Yafei Zhang,Dongni Wang,Ping Sun,Weijun Song,Zexi Jin,Ming Shi,Peng Zhao,Jia Yang,Mingyang Liu,Naixin Wang,Tao Chen,Yong Ji,Bo Yu,Maomao Zhang","doi":"10.1172/jci194664","DOIUrl":"https://doi.org/10.1172/jci194664","url":null,"abstract":"Lactylation, a post-translational modification derived from glycolysis, plays a pivotal role in ischemic heart diseases. Neutrophils are predominantly glycolytic cells that trigger intensive inflammation of myocardial ischemia reperfusion (MI/R). However, whether lactylation regulates neutrophil function during MI/R remains unknown. Employing lactyl proteomics analysis, S100a9 was lactylated at lysine 26 (S100a9K26la) in neutrophils, with elevated levels observed in both acute myocardial infarction (AMI) patients and MI/R model mice. S100a9K26la was demonstrated driving the development of MI/R using mutant knock-in mice. Mechanistically, lactylated S100a9 translocated to the nucleus of neutrophils, where it binded to the promoters of migration-related genes, thereby enhancing their transcription as a co-activator and promoting neutrophil migration and cardiac recruitment. Additionally, lactylated S100a9 was released during NETosis, leading to cardiomyocyte death by disrupting mitochondrial function. The enzyme dihydrolipoyllysine-residue acetyltransferase (DLAT) was identified as the lactyltransferase facilitating neutrophil S100a9K26la post-MI/R, a process that could be restrained by α-lipoic acid. Consistently, targeting DLAT/S100a9K26la axis suppressed neutrophil burden and improved cardiac function post-MI/R. In patients with AMI, elevated S100a9K26la levels in plasma were positively correlated with cardiac death. These findings highlight S100a9 lactylation as a potential therapeutic target for MI/R and as a promising biomarker for evaluating poor prognosis of MI/R.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-17-producing γδ T cells in the tumor microenvironment promote radioresistance in mice.","authors":"Yue Deng,Xixi Liu,Xiao Yang,Wenwen Wei,Jiacheng Wang,Zheng Yang,Yajie Sun,Yan Hu,Haibo Zhang,Yijun Wang,Zhanjie Zhang,Lu Wen,Fang Huang,Kunyu Yang,Chao Wan","doi":"10.1172/jci193945","DOIUrl":"https://doi.org/10.1172/jci193945","url":null,"abstract":"The immunosuppressive tumor microenvironment (TME) drives radioresistance, but the role of γδ T cells in regulating radiosensitivity remains incompletely understood. In this study, we found that γδ T cell infiltration in the TME substantially increased after radiotherapy and contributed to radioresistance. Depletion of γδ T cells enhanced radiosensitivity. Single-cell RNA sequencing revealed that γδ T cells in the post-radiotherapy TME were characterized by the expression of Zbtb16, Il23r, and Il17a, and served as the primary source of IL-17A. These γδ T cells promoted radioresistance by recruiting myeloid-derived suppressor cells and suppressing T cell activation. Mechanistically, radiotherapy-induced tumor cell-derived microparticles containing dsDNA activated the cGAS-STING/NF-κB signaling pathway in macrophages, upregulating the expression of the chemokine CCL20, which was critical for γδ T cell recruitment. Targeting γδ T cells and IL-17A enhanced radiosensitivity and improved the efficacy of radiotherapy combined with anti-PD-1 immunotherapy, providing potential therapeutic strategies to overcome radioresistance.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDKL1 variants affecting ciliary formation predispose to thoracic aortic aneurysm and dissection.","authors":"Theresa Nauth,Melanie Philipp,Sina Renner,Martin D Burkhalter,Helke Schüler,Ceren Saygi,Kristian Händler,Bente Siebels,Alice Busch,Thomas Mair,Verena Rickassel,Sophia Deden,Konstantin Hoffer,Jakob Olfe,Thomas S Mir,Yskert von Kodolitsch,Evaldas Girdauskas,Meike Rybczynski,Malte Kriegs,Hannah Voß,Thomas Sauvigny,Malte Spielmann,Malik Alawi,Susanne Krasemann,Christian Kubisch,Till J Demal,Georg Rosenberger","doi":"10.1172/jci186287","DOIUrl":"https://doi.org/10.1172/jci186287","url":null,"abstract":"Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD-spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Co-injection of human CDKL1wildtype, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularily with ciliary transport molecules. Expression of CDKL1 variants in heterologeous cells interfered with cilia formation and length, CDKL1 localization, and p38-MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD-spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver Syndrome.","authors":"Alyssa F Solano,Kristina Preusse,Brittany Cain,Rebecca Hotz,Parthav Gavini,Zhenyu Yuan,Benjamin Bowen,Gabrielle Maco,Hope Neal,Ellen K Gagliani,Christopher Ahn,Hee-Woong Lim,Laura Southgate,Rhett A Kovall,Raphael Kopan,Brian Gebelein","doi":"10.1172/jci187532","DOIUrl":"https://doi.org/10.1172/jci187532","url":null,"abstract":"Adams-Oliver Syndrome (AOS) is a rare congenital disorder characterized by scalp, limb, and cardiovascular defects. While variants in the NOTCH1 receptor, DLL4 ligand, and RBPJ transcription factor have been implicated in AOS, the driving tissue types and molecular mechanisms by which these variants cause pathogenesis are unknown. Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA. Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include increased lethality and cardiovascular defects in a Notch1 heterozygous background, whereas Notch1 and Rbpj compound heterozygous null alleles are well-tolerated. To facilitate studies into the tissues driving AOS pathogenesis, we employed conditional genetics to isolate the contribution of the vascular endothelium to the development of AOS-like phenotypes. Importantly, our studies show that expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects. These data establish that reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cell-type-specific genetic architecture of chronic pain in brain and dorsal root ganglia.","authors":"Sylvanus Toikumo,Marc Parisien,Michael J Leone,Chaitanya Srinivasan,Huasheng Yu,Asta Arendt-Tranholm,Úrzula Franco-Enzástiga,Christoph Hofstetter,Michele Curatolo,Wenqin Luo,Andreas R Pfenning,Rebecca P Seal,Rachel L Kember,Theodore J Price,Luda Diatchenko,Stephen G Waxman,Henry R Kranzler","doi":"10.1172/jci197583","DOIUrl":"https://doi.org/10.1172/jci197583","url":null,"abstract":"Chronic pain is a complex clinical problem comprising multiple conditions that may share a common genetic profile. Genome-wide association studies (GWAS) have identified many risk loci whose cell-type context remains unclear. Here, we integrated GWAS data on chronic pain (N = 1,235,695) with single-cell RNA sequencing (scRNA-seq) data from human brain and dorsal root ganglia (hDRG), and single-cell chromatin accessibility data from human brain and mouse dorsal horn. Pain-associated variants were enriched in glutamatergic neurons; mainly in prefrontal cortex, hippocampal CA1-3, and amygdala. In hDRG, the hPEP.TRPV1/A1.2 neuronal subtype showed robust enrichment. Chromatin accessibility analyses revealed variant enrichment in excitatory and inhibitory neocortical neurons in brain and in midventral neurons and oligodendrocyte precursor cells in the mouse dorsal horn. Gene-level heritability in the brain highlighted roles for kinase activity, GABAergic synapses, axon guidance, and neuron projection development. In hDRG, implicated genes related to glutamatergic signaling and neuronal projection. In cervical DRG of patients with acute or chronic pain (N = 12), scRNA-seq data from neuronal or non-neuronal cells were enriched for chronic pain-associated genes (e.g., EFNB2, GABBR1, NCAM1, SCN11A). This cell-type-specific genetic architecture of chronic pain across central and peripheral nervous system circuits provides a foundation for targeted translational research.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BAF60a-dependent chromatin remodeling preserves β-cell function and contributes to the therapeutic benefits of GLP-1R agonists.","authors":"Xinyuan Qiu,Ruo-Ran Wang,Qing-Qian Wu,Hongxing Fu,Shuaishuai Zhu,Wei Chen,Wen Wang,Haide Chen,Xiuyu Ji,Wenjing Zhang,Dandan Yan,Jing Yan,Li Jin,Rong Zhang,Mengjie Shi,Ping Luo,Yingqing Yang,Qintao Wang,Ziyin Zhang,Wei Ding,Xiaowen Pan,Chengbin Li,Bin Liang,Guoji Guo,Hai-Long Piao,Min Zheng,Yan Sheng,Lingyun Zhu,Cheng Hu,Zhuo-Xian Meng","doi":"10.1172/jci177980","DOIUrl":"https://doi.org/10.1172/jci177980","url":null,"abstract":"Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β-cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β-cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β-cell function under metabolic stress conditions. BAF60a was downregulated in β-cells from obese and diabetic mice, monkeys, and humans. β-cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β-cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β-cells. A BAF60a V278M mutation associated with decreased β-cell GSIS function was identified in human subjects. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β-cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β-cells critical for glucose sensing and insulin secretion.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urine proteins reveal distinct coagulation and complement cascades underlying acute versus chronic lupus nephritis.","authors":"Ting Zhang,Jessica Castillo,Anto Sam Crosslee Louis Sam Titus,Kamala Vanarsa,Vedant Sharma,Sohan Kureti,Ramesh Saxena,Chandra Mohan","doi":"10.1172/jci186143","DOIUrl":"https://doi.org/10.1172/jci186143","url":null,"abstract":"The current gold standard for assessing renal pathology in lupus nephritis (LN) is invasive and cannot be serially repeated. To assess if urine can serve as a liquid biopsy for underlying renal pathology, urine obtained from patients with LN at the time of renal biopsy were interrogated for 1,317 proteins, using an aptamer-based proteomic screen. Levels of 57 urine proteins were significantly elevated and correlated with pathology activity index (AI), notably endocapillary hypercellularity, fibrinoid necrosis, and cellular crescents. These included proteins pertaining to leukocyte/podocyte activation, neutrophil activation, endothelial activation, and markers of inflammation/anti-inflammation. In contrast, complement and coagulation cascade proteins, and proteins related to the extracellular matrix (ECM) emerged as the strongest urinary readouts of concurrent renal pathology chonicity index (CI), notably tubular atrophy and interstitial fibrosis. In vitro mechanistic studies revealed that complement proteins C3a and C5a increased the expression of profibrotic ECM proteins in macrophages and proximal tubule epithelial cells. Thus, carefully assembled panels of urinary proteins that are indicative of high renal pathology AI and/or CI may help monitor the status of renal pathology after therapy in patients with LN, in a noninvasive manner, without the need for repeat renal biopsies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}