JCI insightPub Date : 2025-06-10eCollection Date: 2025-07-22DOI: 10.1172/jci.insight.188323
Wida Amini, Lena Schemmelmann, Jan-Niklas Heming, Marina Oguama, Katharina Thomas, Helena Block, Pia Lindental, Bernadette Bardel, Andreas Margraf, Oliver Soehnlein, Anika Cappenberg, Alexander Zarbock
{"title":"Csk-mediated Src family kinase regulation dampens neutrophil infiltration during pulmonary infection.","authors":"Wida Amini, Lena Schemmelmann, Jan-Niklas Heming, Marina Oguama, Katharina Thomas, Helena Block, Pia Lindental, Bernadette Bardel, Andreas Margraf, Oliver Soehnlein, Anika Cappenberg, Alexander Zarbock","doi":"10.1172/jci.insight.188323","DOIUrl":"10.1172/jci.insight.188323","url":null,"abstract":"<p><p>Neutrophil recruitment is crucial for pathogen elimination. However, precise control of the inflammatory response prevents overshooting reactions. Neutrophil activation initiates signaling, resulting in integrin β2 (Itgb2) activation and neutrophil arrest. Src family kinases are involved in multiple cellular processes and are negatively regulated by the C-terminal Src kinase (Csk). During this study, we investigated the mechanism by which Csk regulates integrin activation and neutrophil recruitment. Here, we demonstrated that Csk deficiency in murine neutrophils resulted in increased neutrophil adhesion to the endothelium along with decreased neutrophil transmigration into inflamed tissues compared with their littermate controls. In bacterial pneumonia, infected Csk-deficient mice showed higher bacterial burdens and decreased neutrophil recruitment, while other immune cell counts and cytokine levels were not significantly different compared to control. Analyses of Csk-deficient neutrophils revealed an increased Itgb2 affinity, leading to reduced migration and intravascular crawling. Mechanistically, elevated cAMP levels increased protein kinase A activity, which subsequently enhanced Csk activation. Csk, in turn, suppressed Src family kinase activation through phosphorylation (Y529). Hence, Csk-mediated regulation of neutrophil infiltration contributes to maintain a balanced immune response during bacterial pneumonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266241","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}
JCI insightPub Date : 2025-06-10eCollection Date: 2025-07-22DOI: 10.1172/jci.insight.187799
Luis F Flores, David L Marks, Renzo E Vera, Ashley N Sigafoos, Ezequiel J Tolosa, Luciana L Almada, David R Pease, Merih D Toruner, Brian Chang, Brooke R Tader, Kayla C LaRue-Nolan, Ryan M Carr, Rondell P Graham, Catherine E Hagen, Matthew R Brown, Aleksey V Matveyenko, Katherine L Wilson, David W Dawson, Christopher L Pin, Kyle J Roux, Martin E Fernandez-Zapico
{"title":"Emerin is an effector of oncogenic KRAS-driven nuclear dynamics in pancreatic cancer.","authors":"Luis F Flores, David L Marks, Renzo E Vera, Ashley N Sigafoos, Ezequiel J Tolosa, Luciana L Almada, David R Pease, Merih D Toruner, Brian Chang, Brooke R Tader, Kayla C LaRue-Nolan, Ryan M Carr, Rondell P Graham, Catherine E Hagen, Matthew R Brown, Aleksey V Matveyenko, Katherine L Wilson, David W Dawson, Christopher L Pin, Kyle J Roux, Martin E Fernandez-Zapico","doi":"10.1172/jci.insight.187799","DOIUrl":"10.1172/jci.insight.187799","url":null,"abstract":"<p><p>For over a century, scientists reported the disruption of normal nuclear shape and size in cancer. These changes have long been used as tools for diagnosis and staging of malignancies. However, to date, the mechanisms underlying these aberrant nuclear phenotypes and their biological significance remain poorly understood. Using a model of pancreatic ductal adenocarcinoma (PDAC), the major histological subtypes of pancreatic cancer, we found that oncogenic mutant KRAS reduces nuclear size. Transcriptomic and protein expression analysis of mutant KRAS-expressing PDAC cells revealed differential levels of several nuclear envelope-associated genes. Further analysis demonstrated the nuclear lamina protein, Emerin (EMD), acted downstream of KRAS to mediate nuclear size reduction in PDAC. Analysis of human PDAC samples showed that increased EMD expression associates with reduced nuclear size. Finally, in vivo genetic depletion of EMD in a mutant KRAS-driven PDAC model resulted in increased nuclear size and a reduced incidence of poorly differentiated PDAC. Thus, our data provide evidence of a potentially novel mechanism underlying nuclear size regulation and its effect in PDAC carcinogenesis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266257","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}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.184742
Jennifer K Lee, Yue He, Shireen Rl Flores, Regina R Woloshun, Xiaoyu Wang, Jacob S Shine, Pearl O Ebea-Ugwuanyi, Sitara Sriram, Melissa Fraga, Sean Zhu, Yang Yu, Iqbal Hamza, James F Collins
{"title":"Development of rat and mouse models of heme-iron absorption.","authors":"Jennifer K Lee, Yue He, Shireen Rl Flores, Regina R Woloshun, Xiaoyu Wang, Jacob S Shine, Pearl O Ebea-Ugwuanyi, Sitara Sriram, Melissa Fraga, Sean Zhu, Yang Yu, Iqbal Hamza, James F Collins","doi":"10.1172/jci.insight.184742","DOIUrl":"10.1172/jci.insight.184742","url":null,"abstract":"<p><p>Heme iron (HI), derived principally from hemoglobin (Hb) in animal foods, is a highly bioavailable source of dietary iron for humans. Despite several decades of focused research, however, molecular mechanisms governing HI absorption remain undefined. Previous studies in mice and rats have not produced a consensus, definitive model of efficient HI absorption/utilization. We hypothesized that a nutritional approach, using semipurified, HI-containing diets, could be utilized to establish a tractable rodent model of HI absorption that could ultimately be employed to test the roles of receptors, transporters, and enzymes using genetic engineering technology. Experiments were designed to assess HI utilization by feeding animals AIN-93G-based, HI-enriched experimental diets formulated with lyophilized porcine RBCs, containing approximately 85% HI and 15% nonheme iron (NHI). Total iron was within the physiological range (50-75 ppm) and precisely matched NHI control diets containing ferrous sulfate were utilized as comparators. Notably, in Sprague-Dawley (S-D) rats and C57BL/6 (B6) mice, dietary HI effectively (a) resolved iron-deficiency anemia; (b) supported normal pregnancy, lactation, and neonatal development; and (c) contributed to iron loading in Hamp-KO mice and rats (modeling hereditary hemochromatosis). A nutritional paradigm has thus been established that facilitates investigation into mechanisms of HI absorption by S-D rats and B6 mice.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.184968
Lu Ji, Leighton Pu, Jinglong Wang, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E Laseinde, Rie von Eyben, Sara A Richter, Jin-Min Nam, Christina Kong, Kerriann M Casey, Edward E Graves, Richard L Frock, Quynh Thu Le, Erinn B Rankin
{"title":"FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer.","authors":"Lu Ji, Leighton Pu, Jinglong Wang, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E Laseinde, Rie von Eyben, Sara A Richter, Jin-Min Nam, Christina Kong, Kerriann M Casey, Edward E Graves, Richard L Frock, Quynh Thu Le, Erinn B Rankin","doi":"10.1172/jci.insight.184968","DOIUrl":"10.1172/jci.insight.184968","url":null,"abstract":"<p><p>Despite aggressive chemoradiation treatment, the overall survival rate for patients with HPV- head and neck squamous cell carcinoma (HNSCC) remains poor, highlighting the urgent need for more effective drug-radiotherapy combinations to improve the therapeutic index of radiation therapy (RT). The fat mass and obesity-related gene (FTO) is emerging as a promising cancer therapeutic target; however, its role in the RT response has been underexplored. In our study, we found that both genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in human and mouse HNSCC tumor xenografts. Mechanistically, inhibition of FTO improved the RT response in HPV- HNSCC cells, which was associated with increased DNA damage, reduced efficiency of homology directed repair, and decreased formation of RAD51 homolog 1 (RAD51) foci. Importantly, pharmacologic inhibition of FTO did not exacerbate radiation-induced oral mucositis, a significant normal-tissue toxicity associated with HNSCC RT. In summary, our results indicate a role for FTO in regulating homologous recombination while identifying FTO as a potential therapeutic target to enhance the therapeutic index of RT in HPV- HNSCC treatment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.188325
Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A Matthay
{"title":"The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung.","authors":"Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A Matthay","doi":"10.1172/jci.insight.188325","DOIUrl":"10.1172/jci.insight.188325","url":null,"abstract":"<p><p>Bacterial pneumonia is the most common cause of acute respiratory distress syndrome (ARDS), characterized by disrupted pulmonary endothelial barrier function, hyperinflammation, and impaired alveolar epithelial fluid clearance. ARDS has a high mortality rate and no proven pharmacological treatments, stressing the need for new targeted therapies. The TIP peptide, mimicking the lectin-like domain of TNF, directly binds to the α subunit of the epithelial Na+ channel, expressed in both alveolar epithelial and capillary endothelial cells, and may increase lung endothelial barrier function and alveolar fluid clearance during bacterial infection. This study tested these potential therapeutic mechanisms of the TIP peptide in a clinically relevant preparation of the ex vivo-perfused human lung injured by Streptococcus pneumoniae. Therapeutic administration of the TIP peptide reduced pulmonary barrier permeability to protein and lung edema formation, increased alveolar edema fluid clearance, and produced an antiinflammatory effect in the airspaces with reductions in IL-6 and IL-8 levels. Additionally, the TIP peptide reduced the translocation of bacteria into the circulation. These findings establish 3 mechanisms of benefit with the TIP peptide to reduce injury in the human lung and support the clinical relevance as a potential therapeutic for pneumococcal bacterial pneumonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.190648
Paul E George, Grace Kalmus, Joseph Lipscomb, David H Howard, Benjamin Kopp, Wilbur A Lam, Stefanie Ebelt
{"title":"Annual PM2.5 exposure and clinical, laboratory, and stroke-risk outcomes in pediatric sickle cell disease.","authors":"Paul E George, Grace Kalmus, Joseph Lipscomb, David H Howard, Benjamin Kopp, Wilbur A Lam, Stefanie Ebelt","doi":"10.1172/jci.insight.190648","DOIUrl":"10.1172/jci.insight.190648","url":null,"abstract":"<p><p>Sickle cell disease (SCD) causes severe morbidity and early mortality, yet it varies phenotypically. Both air pollution and SCD affect the cardiorespiratory, inflammatory, and endothelial systems; however, limited evidence exists on the effect of long-term air pollution exposure in SCD. We hypothesized that annual ambient (outdoor) concentrations of fine particulate matter (PM2.5), particles with a diameter of 2.5 μm or less, at a child's home would be significantly associated with worse clinical, laboratory, and stroke-risk imaging outcomes. Patient data for this retrospective study were obtained from a cohort of children with SCD (from 2010 to 2019). Annual PM2.5 exposure was estimated using remote-sensing air pollution datasets. Statistical analyses employed fixed effects multivariable models, offering a robust approach to isolate the effect of PM2.5 exposure. The final cohort included 1,089 children with SCD. Higher annual PM2.5 concentrations were significantly associated with more annual hospital days, higher likelihood of hospitalization and abnormal stroke-risk screening, and elevated inflammatory markers. Of note, hydroxyurea use mitigated the inflammatory response to PM2.5 but did not mitigate the effect of PM2.5 on clinical outcomes. Importantly, the elevated stroke risk associated with PM2.5 exposure persisted, even among children receiving hydroxyurea therapy, highlighting a critical concern in pediatric SCD management. These results underscore the clinical importance of addressing environmental factors for comprehensive SCD care.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.184843
Katie L Alexander, Kelsey B Bennion, Danya Liu, Mandy L Ford
{"title":"CD154:CD11b blockade enhances CD8+ T cell differentiation during infection but not transplantation.","authors":"Katie L Alexander, Kelsey B Bennion, Danya Liu, Mandy L Ford","doi":"10.1172/jci.insight.184843","DOIUrl":"10.1172/jci.insight.184843","url":null,"abstract":"<p><p>CD154 is a promising target for immunosuppression in transplantation, autoimmunity, and inflammatory diseases. We previously identified CD11b as a novel alternative receptor for CD154 during alloimmunity. However, the impact of specific CD154:CD11b blockade on immune responses to infection has not been well characterized. Here, we have shown that in contrast with its immunosuppressive effect on graft-specific CD8+ T cells, CD154:CD11b blockade unexpectedly improved both the quantity and quality of murine herpesvirus-68-specific CD8+ T cells as measured by an increase in tetramer-positive KLRG1loCD127hi memory precursor effector cells. The differential effect of CD154:CD11b blockade on graft- versus virus-specific CD8+ T cells was underpinned by differences in phosphorylated S6 downstream of mTOR complex 1; however, differential expression of key transcription factors Eomes and TCF-1 was dictated by the type of antigen stimulus. These data demonstrate that priming conditions play an important role in determining the outcome of immunotherapy and suggest that specific inhibition of CD154:CD11b interactions could be effective for suppressing alloimmune responses while maintaining protective immunity to minimize infectious complications following transplantation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"De novo variant in RING finger protein 213 causes systemic vasculopathy.","authors":"Ayako Kashimada, Tomoko Mizuno, Eriko Tanaka, Susumu Hosokawa, Tomohiro Udagawa, Yuichi Hiraoka, Keisuke Uchida, Tomohiro Morio, Kenjiro Kosaki, Masatoshi Takagi","doi":"10.1172/jci.insight.190094","DOIUrl":"10.1172/jci.insight.190094","url":null,"abstract":"<p><p>Systemic arterial stenosis, including moyamoya disease (MMD) and middle aortic syndrome (MAS), is a rare condition of unclear etiology. MMD is a cerebral angiopathy, and MAS affects the abdominal and thoracic aorta. Although some genetic associations with MAS have been identified, the causes remain elusive. In this study, de novo heterozygous missense variants of RING finger protein 213 (RNF213) (p.His4058Pro and p.Thr4155Pro) in 2 unrelated families with MAS and MMD were studied by whole-exome sequencing. To elucidate the significance of these variants, we produced knockin mice carrying the Rnf213 p.His4058Pro variant. Homozygous knockin mice exhibited perinatal lethality because of respiratory failure and lung dysplasia, suggesting that this variant is pathogenic. Lung dysplasia in homozygous knockin mice was associated with upregulated innate immunity and inflammatory responses and downregulated cell proliferation. These findings suggested that in mice, the RNF213 p.His4058Pro variant plays critical roles in regulation of innate immunity and inflammation that affect lung development, revealing the complexity of RNF213 function in various tissues and species. In conclusion, this study provides insights into the genetic basis of MAS and MMD, highlights the potential involvement of RNF213 variants in systemic vasculopathy, and identifies unexpected associations with lung development and immune processes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-09DOI: 10.1172/jci.insight.189343
Xiaodun Yang, Angela Zanfardino, Riccardo Schiaffini, Jeff Ishibashi, Bareket Daniel, Matthew W Haemmerle, Novella Rapini, Alessia Piscopo, Emanuele Miraglia Del Giudice, Maria Cristina Digilio, Raffaele Iorio, Mafalda Mucciolo, Stefano Cianfarani, Dario Iafusco, Fabrizio Barbetti, Doris A Stoffers
{"title":"Neonatal diabetes-associated missense PDX1 variant disrupts chromatin association and protein-protein interaction.","authors":"Xiaodun Yang, Angela Zanfardino, Riccardo Schiaffini, Jeff Ishibashi, Bareket Daniel, Matthew W Haemmerle, Novella Rapini, Alessia Piscopo, Emanuele Miraglia Del Giudice, Maria Cristina Digilio, Raffaele Iorio, Mafalda Mucciolo, Stefano Cianfarani, Dario Iafusco, Fabrizio Barbetti, Doris A Stoffers","doi":"10.1172/jci.insight.189343","DOIUrl":"10.1172/jci.insight.189343","url":null,"abstract":"<p><p>PDX1 mutations are associated with multiple forms of diabetes, including syndromic, neonatal, mature onset diabetes of the young (MODY), and type 2 diabetes. Two PDX1 missense mutations (Thr151Met and Asn196Thr) were identified in a pediatric female patient that cause permanent neonatal diabetes, pancreas hypoplasia, and a malformed gallbladder. We found that the mouse Pdx1 Asn197Thr variant (homologous to human PDX1 Asn196Thr), but not Pdx1 Thr152Met (homologous to human PDX1 Thr151Met), altered its nuclear localization and disrupted the PDX1-ONECUT1 interaction. Neither variant substantially affected PDX1 protein stability, but both reduced PDX1 binding to the Pdx1 gene promoter. Importantly, the Pdx1 Asn197Thr variant caused pancreas agenesis and reduced enteroendocrine cells in the duodenum in genetically engineered mice, due at least in part to reduced Pdx1 promoter binding and disrupted PDX1-ONECUT1 interaction.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 11","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-06-05eCollection Date: 2025-07-08DOI: 10.1172/jci.insight.190992
Hasan Demirci, Jessica P Bahena-Lopez, Alina Smorodchenko, Xiao-Tong Su, Jonathan W Nelson, Chao-Ling Yang, Joshua N Curry, Xin-Peng Duan, Wen-Hui Wang, Yuliya Sharkovska, Ruisheng Liu, Duygu Elif Yilmaz, Catarina Quintanova, Katie Emberley, Ben Emery, Nina Himmerkus, Markus Bleich, David H Ellison, Sebastian Bachmann
{"title":"Distinct cell types along thick ascending limb express pathways for monovalent and divalent cation transport.","authors":"Hasan Demirci, Jessica P Bahena-Lopez, Alina Smorodchenko, Xiao-Tong Su, Jonathan W Nelson, Chao-Ling Yang, Joshua N Curry, Xin-Peng Duan, Wen-Hui Wang, Yuliya Sharkovska, Ruisheng Liu, Duygu Elif Yilmaz, Catarina Quintanova, Katie Emberley, Ben Emery, Nina Himmerkus, Markus Bleich, David H Ellison, Sebastian Bachmann","doi":"10.1172/jci.insight.190992","DOIUrl":"10.1172/jci.insight.190992","url":null,"abstract":"<p><p>Kidney thick ascending limb (TAL) cells reabsorb sodium, potassium, calcium, and magnesium and contribute to urinary concentration. These cells are typically viewed as a single type that recycles potassium across the apical membrane and generates a lumen-positive transepithelial voltage driving calcium and magnesium reabsorption, though variability in potassium channel expression has been reported. Additionally, recent transcriptomic analyses suggest that different cell types exist along this segment, but classifications have varied and have not led to a new consensus model. We used immunolocalization, electrophysiology, and enriched single-nucleus RNA-Seq to identify TAL cell types in rats, mice, and humans. We identified 3 major TAL cell types defined by expression of potassium channels and claudins. One has apical potassium channels, has low basolateral potassium conductance, and is bordered by a monovalent cation-permeable claudin. A second lacks apical potassium channels, has high basolateral potassium conductance, and is bordered by calcium- and magnesium-permeable claudins. A third type also lacks apical potassium channels and has high basolateral potassium conductance, but these cells are ringed by monovalent cation-permeable claudins. The recognition of diverse cell types may resolve longstanding questions about how solute transport can be modulated selectively and how disruption of these cells leads to human disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234115","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}
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