JCI insightPub Date : 2026-09-22DOI: 10.1172/jci.insight.205467
Gabriel F Batzli, Kaiying Guo, Fahrünisa Meryem Betül Erol, Charles A LeDuc, Lisa C Burnett, Rudolph L Leibel, Yiying Zhang
{"title":"Role of Snord116 in pituitary growth hormone deficiency of Prader-Willi syndrome.","authors":"Gabriel F Batzli, Kaiying Guo, Fahrünisa Meryem Betül Erol, Charles A LeDuc, Lisa C Burnett, Rudolph L Leibel, Yiying Zhang","doi":"10.1172/jci.insight.205467","DOIUrl":"10.1172/jci.insight.205467","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) is a complex genetic disorder resulting from the deficiency of several maternally imprinted genes, including SNORD116, in the 15q11-q13 region. Loss of Snord116 in mice recapitulates some of the most salient clinical features of PWS, including growth hormone (GH) deficiency and hypogonadism. This study explored the impact of Snord116 deficiency on early postnatal pituitary development and growth in Snord116-KO mice. Snord116 was found to be expressed in both the anterior and posterior pituitary. Pituitary transcriptomes of Snord116-KO and WT mice at 2 developmental stages, P0 and 4 weeks of age, were interrogated and related to ex vivo analyses of GH secretion in the pituitaries of 5-week-old mice. Significant differences in pituitary transcriptomes were detected between Snord116-KO and WT mice at 4 weeks of age but not at P0. The differentially expressed genes and affected molecular pathways play important roles in regulating embryonic and postnatal pituitary development. Our results suggested that PWS GH deficiency was mainly due to pituitary hypoplasia and decreased GH production but not to reduced GH secretory function per se, implicating Snord116 in the specific molecular/cellular pathways that account for impaired postnatal pituitary development and GH deficiency in PWS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016821","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 : 2026-09-22DOI: 10.1172/jci.insight.203086
Craig A Emter, Marcus Henze, Mike DuVall, Sarah Lehman, Lindsey Lee, Ben Barthel, Natalie A Hawryluk, Molly Madden, Yangsong Wu, Amy Perry, Martin Beyer, Eric Wei, Cassady Rupert, Steve Roof, Angela Peter, Emily DiNatale, Sara Cantrell, Jessica Tolley, Stephen Schlachter, Jolanda van der Velden, Michelle Michels, Christine Seidman, Weikang Ma, Leslie Leinwand, Stuart Campbell, Julien Ochala, David Bluemke, Darla Tharp, Jonathan Seidman, Carlos L Del Rio, Marc Semigran, Marc Evanchik, Kevin Koch, Alan Russell
{"title":"Mechanistic diversity within RLC-dependent myosin ATPase inhibitors differentiates EDG-7500, a diastolic-selective cardiac sarcomere modulator.","authors":"Craig A Emter, Marcus Henze, Mike DuVall, Sarah Lehman, Lindsey Lee, Ben Barthel, Natalie A Hawryluk, Molly Madden, Yangsong Wu, Amy Perry, Martin Beyer, Eric Wei, Cassady Rupert, Steve Roof, Angela Peter, Emily DiNatale, Sara Cantrell, Jessica Tolley, Stephen Schlachter, Jolanda van der Velden, Michelle Michels, Christine Seidman, Weikang Ma, Leslie Leinwand, Stuart Campbell, Julien Ochala, David Bluemke, Darla Tharp, Jonathan Seidman, Carlos L Del Rio, Marc Semigran, Marc Evanchik, Kevin Koch, Alan Russell","doi":"10.1172/jci.insight.203086","DOIUrl":"10.1172/jci.insight.203086","url":null,"abstract":"<p><p>Small molecules that modulate myofibril ATPase activity via the myosin regulatory light chain (RLC) display a broad spectrum of activity in their ability to enhance relaxation and slow contraction. EDG-7500 exhibits features consistent with a 'diastolic-selective' cardiac sarcomere modulator (d-CSM), and its ability to treat HCM was explored in engineered human tissue (EHT), human HCM cardiac strips, and an R403Q mutation swine model. In fibers, EDG-7500 preferentially inhibited myofibril ATPase activity and force at diastolic calcium levels, retained length-dependent force activation, accelerated relaxation, and exhibited a shallow, self-limiting inhibitory-exposure response to LV fractional shortening. Compared to CMIs, EDG-7500 moved myosin heads towards the thin filament and accelerated relaxation without decreasing force in mutated EHTs (R403Q). In human HCM cardiac strips, EDG-7500 did not alter myosin SRX state, but decreased Ca2+-sensitivity of force independent of mutation. In R403Q swine, chronic EDG-7500 normalized LV filling pressure and prevented pathological cardiac remodeling while preserving normal systolic function and cardiac reserve. EDG-7500 differentiates itself from CMIs by uniquely targeting both phases of the cardiac cycle, improving ventricular relaxation while preserving systolic function. This suggests optimal diastolic efficacy can be reached without balancing systolic impairment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016824","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 : 2026-09-22DOI: 10.1172/jci.insight.209036
Payal Kapur, Daria Beshnova, Hua Zhong, Ruby Sharma, Pooja Ghatalia, Angela Yoo, Daniel D Le, Ratna Mukhopadhyay, Alana Christie, Jeffrey Miyata, Shuanzeng Wei, Rana R McKay, Dinesh Rakheja, Satwik Rajaram, Robert G Uzzo, A Ari Hakimi, Zora Modrusan, James Brugarolas
{"title":"Molecular underpinnings of metastatic small renal masses.","authors":"Payal Kapur, Daria Beshnova, Hua Zhong, Ruby Sharma, Pooja Ghatalia, Angela Yoo, Daniel D Le, Ratna Mukhopadhyay, Alana Christie, Jeffrey Miyata, Shuanzeng Wei, Rana R McKay, Dinesh Rakheja, Satwik Rajaram, Robert G Uzzo, A Ari Hakimi, Zora Modrusan, James Brugarolas","doi":"10.1172/jci.insight.209036","DOIUrl":"10.1172/jci.insight.209036","url":null,"abstract":"<p><p>Metastases in renal cell carcinoma (RCC) typically arise from large primary tumors. However, a subset of patients with small renal masses (SRMs; ≤4 cm) can develop metastatic disease. Identifying these tumors is clinically important, as many SRMs are managed with active surveillance, and their study may provide insight into the early acquisition of metastatic competence. It remains unclear whether these tumors acquire distinct metastatic programs or instead show premature activation of the same aggressive programs typically associated with larger tumors. Here, we performed integrated morphological and molecular profiling of a multiinstitutional cohort of metastatic SRMs, including whole-exome sequencing and RNA-Seq, using nonmetastatic primary tumors as controls. Among metastatic, non-clear cell SRMs, we identified NF2-altered tumors, ELOC-mutated RCC, and an mTOR-driven eosinophilic vacuolated tumor. Metastatic clear cell SRMs were enriched by multi-hit aggressive genotypes, including recurrent losses of chromosomes 8p, 9, and 14q, as well as co-occurring driver alterations (≥2 events), including BAP1 and mTOR pathway genes. Transcriptomic analyses revealed enrichment of the non-negative matrix factorization 3 (NMF3) subtype from the IMmotion151 trial-based taxonomy, along with metabolic rewiring and reduced cytotoxic immune effector function. Collectively, these findings identify molecular programs associated with metastatic competence in SRMs, highlight the importance of genomic studies of equivocal non-clear cell SRMs, and provide a biological framework for risk stratification in patients often considered for active surveillance.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016788","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 : 2026-09-22DOI: 10.1172/jci.insight.208692
Elisabetta Granato, Xiaoyun Wang, Yun Zhang, Joselyn Rojas-Quintero, Ida Cerqua, Scott A Ochsner, Jeff Thomas Kue, Luca Cecchetto, Maor Sauler, Farrah Kheradmand, Joshua Malo, Fiorentina Roviezzo, Irina Petrache, Francesca Polverino
{"title":"Sphingolipid metabolism contributes to sex dimorphism in COPD pathogenesis.","authors":"Elisabetta Granato, Xiaoyun Wang, Yun Zhang, Joselyn Rojas-Quintero, Ida Cerqua, Scott A Ochsner, Jeff Thomas Kue, Luca Cecchetto, Maor Sauler, Farrah Kheradmand, Joshua Malo, Fiorentina Roviezzo, Irina Petrache, Francesca Polverino","doi":"10.1172/jci.insight.208692","DOIUrl":"https://doi.org/10.1172/jci.insight.208692","url":null,"abstract":"<p><p>Sex-specific mechanisms in chronic obstructive pulmonary disease (COPD) remain poorly defined. Sphingolipids are bioactive mediators that regulate airway epithelial integrity, inflammation, and bronchial smooth muscle tone, and their dysregulation contributes to airway hyperresponsiveness. We tested whether sphingolipid metabolism is regulated by sex in COPD. Lung tissue and paired plasma from female and male never-smoking controls (NSC), ever-smoking controls (SC), and COPD subjects were analyzed for sphingolipid enzyme expression and metabolite levels. Bronchial rings from mice and human bronchial smooth muscle cells (HBSMCs) were exposed to estradiol or cigarette smoke extract (CSE) ± ceramidase or sphingosine kinase inhibitors. Expression of sphingolipid regulators ASAH1 and ORMDL3 was increased in COPD airways, significantly higher in women, and correlated with airway smooth muscle remodeling. Plasma from females with COPD showed increased sphingosine-1-phosphate (S1P), whereas males exhibited higher ceramide levels. Female mice displayed greater CSE-induced bronchial reactivity, attenuated by sphingosine kinase inhibition. In male-donor HBSMCs, estradiol increased ASAH1, ORMDL3, S1P, and smooth muscle protein expression and enhanced contractility. CSE further augmented molecular responses in estradiol-treated cells but reduced collagen-gel contraction, whereas ceramidase inhibition attenuated estradiol-dependent effects. These findings suggest that estrogen-dependent alterations in sphingolipid metabolism contribute to airway hyperreactivity and remodeling in females with COPD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024868","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":"Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation.","authors":"Yoshitsugu Oikawa, Yuhan Luo, Naoki Suzuki, Tomoko Kasahara, Yoshiyasu Tongu, Yuki Yoshida, Tsukasa Tominari, Shogo Tanabe, Yoshiko Suto, Hitomi Kashiwagi, Saki Saito, Kensuke Ikeda, Chitose Suzuki, Arata Kuranaga, Tetsuya Akiyama, Satoru Morimoto, Yoshitsugu Aoki, Rieko Muramatsu, Tomoyoshi Soga, Masashi Aoki, Hideyuki Okano, Tetsuhiro Tanaka, Takaaki Abe, Erina Kuranaga, Takafumi Toyohara","doi":"10.1172/jci.insight.200761","DOIUrl":"10.1172/jci.insight.200761","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016765","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 : 2026-09-22DOI: 10.1172/jci.insight.199896
Mostafa M Eltobgy, Mohamed M Shamseldin, Owen D Whitham, Heba M Amer, Jeffrey R Atkinson, Asmaa Badr, Jesse M Hall, Gauruv Gupta, Yara Y Hassan, Rabab El-Mergawy, Richard Perez, Sarah E Faber, Maciej Pietrzak, Amy Webb, Xiaoli Zhang, Adam D Kenney, Destiny Bissell, Jihad I Omran, Shady Estfanous, Kylene P Daily, Amir Yousif, Marisa R Joldrichsen, Andrew McNamara, Mahesh Kc, Mark E Peeples, Emily A Hemann, Hazem E Ghoneim, Shahid M Nimjee, Estelle Cormet-Boyaka, Jianrong Li, Prosper N Boyaka, Jacob S Yount, Benjamin M Segal, Purnima Dubey, Amal O Amer
{"title":"Caspase-11-mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection.","authors":"Mostafa M Eltobgy, Mohamed M Shamseldin, Owen D Whitham, Heba M Amer, Jeffrey R Atkinson, Asmaa Badr, Jesse M Hall, Gauruv Gupta, Yara Y Hassan, Rabab El-Mergawy, Richard Perez, Sarah E Faber, Maciej Pietrzak, Amy Webb, Xiaoli Zhang, Adam D Kenney, Destiny Bissell, Jihad I Omran, Shady Estfanous, Kylene P Daily, Amir Yousif, Marisa R Joldrichsen, Andrew McNamara, Mahesh Kc, Mark E Peeples, Emily A Hemann, Hazem E Ghoneim, Shahid M Nimjee, Estelle Cormet-Boyaka, Jianrong Li, Prosper N Boyaka, Jacob S Yount, Benjamin M Segal, Purnima Dubey, Amal O Amer","doi":"10.1172/jci.insight.199896","DOIUrl":"10.1172/jci.insight.199896","url":null,"abstract":"<p><p>Severe SARS-CoV-2 infection is characterized by lung hyperinflammation, impaired IFN responses, and defective T cell activation, yet the molecular drivers of these immune dysregulations remain incompletely understood. Caspase-11 (CASP11), a key effector of the noncanonical inflammasome, has been shown to mediate an innate hyperinflammatory response and cytokine release in a mild SARS-CoV-2 infection model. However, the role played by CASP11 in severe SARS-CoV-2 disease and how it affects adaptive immunity has not been identified. Here, we found that CASP11 exacerbates severe SARS-CoV-2 pathogenesis by amplifying early innate immune responses while concurrently impairing antiviral CD8+ T cell immunity. Using global KO mice, hematopoietic BM chimeras, and Cx3cr1-expressing mononuclear phagocyte system cell-specific CASP11 deletion models, we show that targeting CASP11 reduces lung inflammation, promotes early NK cell-mediated IFN-γ production, and enhances robust virus-specific effector CD8+ T cell responses. This was associated with enhanced viral clearance and improved survival, even under lethal infection conditions. Importantly, CASP11-KO mice also exhibited faster resolution of postviral inflammation. These findings position CASP11 as a promising immunomodulatory target for acute and delayed manifestations of severe SARS-CoV-2 infection.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016801","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 : 2026-09-22DOI: 10.1172/jci.insight.189205
Hong Li, Matthew L Edin, Daniel Menendez, J Alyce Bradbury, Joan P Graves, Artiom Gruzdev, Gregory S Whitehead, Maria I Sifre, Laura M DeGraff, Darryl C Zeldin
{"title":"Cyclooxygenase-2 negatively regulates innate lymphoid cell type 2 differentiation and function during allergic lung inflammation.","authors":"Hong Li, Matthew L Edin, Daniel Menendez, J Alyce Bradbury, Joan P Graves, Artiom Gruzdev, Gregory S Whitehead, Maria I Sifre, Laura M DeGraff, Darryl C Zeldin","doi":"10.1172/jci.insight.189205","DOIUrl":"10.1172/jci.insight.189205","url":null,"abstract":"<p><p>Type 2 innate lymphoid cells (ILC2) are a population of lineage-negative cells in the lung, gastrointestinal tract, and skin which have emerged as a significant component of type 2 allergic inflammation. The regulation of cyclooxygenase-2 (COX-2) metabolites is critical to the pathophysiology of many inflammatory disorders, including allergic asthma. While COX-2 regulates Th9 and Th17 cell differentiation and function during allergic lung inflammation, it remains unknown whether COX-2 also regulates ILC2 cell differentiation and function under similar conditions. To address this question, we examined lung ILC2 cells from COX-2+/+ and COX-2-/- mice after ovalbumin (OVA)- or Alternaria-induced allergic lung inflammation. ILC2 cells were significantly increased in COX-2-/- lungs compared with COX-2+/+ lungs after OVA exposure in vivo. The increase in ILC2 cells was accompanied by an increase in expression of the cytokines IL-5 and IL-13, and the transcription factor GATA3. Both genetic disruption and selective inhibition of COX-2 significantly increased ILC2 cell differentiation from isolated common lymphoid progenitor cells (CLP) in vitro. Furthermore, COX-2-derived PGE2 acting via EP2 receptors significantly reduced IL-33 and TSLP expression, and attenuated ILC2 cell differentiation in vitro and in vivo. Thus, during allergic lung inflammation, COX-2-derived PGE2 signals through the EP2 receptor to negatively regulate lung ILC2 cell differentiation and function.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024846","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 : 2026-09-22DOI: 10.1172/jci.insight.204483
Hyun Ju Lee, Jung Hwa Ko, Joo Youn Oh
{"title":"IL-1R2+ neutrophils define an early sterile injury-expanded subset that restrains inflammation and promotes repair.","authors":"Hyun Ju Lee, Jung Hwa Ko, Joo Youn Oh","doi":"10.1172/jci.insight.204483","DOIUrl":"https://doi.org/10.1172/jci.insight.204483","url":null,"abstract":"<p><p>Sterile tissue injury triggers a rapid neutrophil response that can be either pathogenic or protective, reflecting substantial functional heterogeneity of neutrophils; however, the neutrophil subsets underlying these divergent functions remain poorly defined. Here, using a well-established sterile corneal injury model, we delineate the time-dependent functional and transcriptional heterogeneity of neutrophils following sterile injury. Temporal neutrophil depletion revealed that neutrophils recruited at day 1, but not day 7, are essential for suppressing inflammation, promoting epithelial healing, and preserving nerve density. Single-cell RNA sequencing uncovered substantial transcriptional heterogeneity among circulating neutrophils and their rapid reprogramming within 24 hours after injury. Specifically, Il1r2 was highly enriched in these early injury-responsive neutrophils. Functional validation demonstrated that adoptive transfer of IL-1R2+ neutrophils markedly attenuated inflammation and accelerated epithelial and nerve repair, restoring tissue integrity, whereas IL-1R2- neutrophils exacerbated inflammatory responses. Together, these findings identify IL-1R2+ neutrophils as an early protective neutrophil subset expanded by sterile injury that restrains excessive inflammation and preserves tissue homeostasis, providing mechanistic insight into injury-induced neutrophil reprogramming and highlighting a potential therapeutic target for enhancing tissue repair.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024799","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 : 2026-09-22DOI: 10.1172/jci.insight.179960
Jacqueline M Emathinger, Zhidan Xiang, Jonathan W Nelson, Matthew W Hagen, Nakyung Kim, David I Ortiz-Melo, Natalie Mattocks, Jorge F Giani, Dexter L Lee, Hannah Hartman-Houstman, Donna L Ralph, Alicia A McDonough, Brianna Chen, Stan G Louie, Thomas M Coffman, Susan B Gurley
{"title":"Proximal tubule ACE2 mediates early responses to hypertension by regulating intrarenal RAS and sodium homeostasis.","authors":"Jacqueline M Emathinger, Zhidan Xiang, Jonathan W Nelson, Matthew W Hagen, Nakyung Kim, David I Ortiz-Melo, Natalie Mattocks, Jorge F Giani, Dexter L Lee, Hannah Hartman-Houstman, Donna L Ralph, Alicia A McDonough, Brianna Chen, Stan G Louie, Thomas M Coffman, Susan B Gurley","doi":"10.1172/jci.insight.179960","DOIUrl":"10.1172/jci.insight.179960","url":null,"abstract":"<p><p>ACE2 is a membrane-bound monocarboxypeptidase strongly expressed in the renal proximal tubule (PT) with high affinity to degrade the vasopressor angiotensin II (AngII). We employed a mouse model of PT-specific ACE2 deletion (PT ACE2-KO) to demonstrate that the renal PT is a critical site for ACE2 regulation of blood pressure (BP) via modulation of the intrarenal renin-angiotensin system (RAS). While deletion of ACE2 from the PT had a minimal effect on baseline physiology, PT ACE2-KO mice were more susceptible to AngII hypertension than control mice. At day 5 of AngII infusion, the enhanced BP response was associated with cardiac hypertrophy, increased renal AngII levels, failure to suppress epithelial sodium channel (ENaC) γ cleavage, and increased sodium pump activity in PT ACE2-KO mice. Control mice instead increased renal ACE2 expression to reduce renal AngII accumulation and suppress intrarenal RAS activation, which offered protection from hypertension and complications. Transcriptional analysis corroborated changes in intrarenal RAS components and revealed alterations in distinct physiological pathways during AngII hypertension in PT ACE2-KO mice. Our studies provide evidence for alterations in ENaC regulation to contribute to the development of AngII hypertension and support PT-derived ACE2 as an integral member of the intrarenal RAS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016744","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 : 2026-09-22DOI: 10.1172/jci.insight.203911
Avery M Bogart, Anisa S Haffizulla, Jason Lin, Nathan D Putz, Han Noo Ri Lee, David M Aslaner, Samantha K Gonski, Nancy Wickersham, Kyle Riedmann, Jamie E Meegan, Kaori Oshima, Ciara M Shaver, Julie A Bastarache, Eric P Schmidt, Lorraine B Ware
{"title":"Cell-free hemoglobin upregulates pulmonary endothelial heparanase expression to drive glycocalyx destruction and inflammation in sepsis.","authors":"Avery M Bogart, Anisa S Haffizulla, Jason Lin, Nathan D Putz, Han Noo Ri Lee, David M Aslaner, Samantha K Gonski, Nancy Wickersham, Kyle Riedmann, Jamie E Meegan, Kaori Oshima, Ciara M Shaver, Julie A Bastarache, Eric P Schmidt, Lorraine B Ware","doi":"10.1172/jci.insight.203911","DOIUrl":"https://doi.org/10.1172/jci.insight.203911","url":null,"abstract":"<p><p>Both elevated plasma cell-free hemoglobin (CFH) and heparanase-driven endothelial glycocalyx shedding are contributors to microvascular dysfunction and organ injury in sepsis. However, the mechanisms governing heparanase activation, and the potential role of CFH in this process, are not understood. Utilizing patient samples, mice with cecal slurry-induced (CS) peritonitis and elevated CFH, and human lung microvascular endothelial cells (HLMVECs), we tested the hypothesis that CFH upregulates heparanase production to drive endothelial glycocalyx degradation. In human sepsis, elevated circulating CFH was associated with higher heparanase and heparan sulfate levels, which in turn correlated with adverse clinical outcomes. CS+CFH-treated mice had increased plasma heparanase, glycocalyx degradation, and pulmonary and systemic inflammation; endothelial heparanase deletion abrogated these effects. Additionally, in both pulmonary endothelial cells isolated from CS+CFH-treated mice and HLMVECs exposed to CFH and TNF, heparanase transcription and active enzyme production were increased. The deleterious effects of CFH were attenuated by acetaminophen, a hemoprotein reductant. In summary, we demonstrate that CFH oxidation stimulates endothelial heparanase expression and activation during sepsis, leading to endothelial glycocalyx degradation, which may disrupt the endothelial barrier and result in organ injury. Our findings highlight the CFH-heparanase axis as a potential therapeutic target for endothelial glycocalyx preservation in sepsis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024790","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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