American journal of physiology. Cell physiology最新文献

{"title":"Muscle memory of exercise optimizes mitochondrial metabolism to support skeletal muscle growth.","authors":"Clay J Weidenhamer, Yi-Heng Huang, Subhashis Natua, Auinash Kalsotra, Diego Hernández-Saavedra","doi":"10.1152/ajpcell.00451.2025","DOIUrl":"10.1152/ajpcell.00451.2025","url":null,"abstract":"<p><p>Exercise protects against age-related declines in skeletal muscle mass and function while improving overall health. Exercise can also prime long-term muscle health to enhance adaptations upon exercise retraining, a phenomenon termed muscle memory that remains largely understudied. To assess how prior endurance training elicits a lasting metabolic memory in skeletal muscle, we used C57BL/6 mice fed either a control (CD) or obesogenic diet [high-fat diet (HFD)] that underwent 4-wk training, detraining, and retraining periods. Our results show that exercise retraining attenuated weight gain and potentiated muscle growth, even with reduced voluntary running volumes. Training increased fiber size [fiber cross-sectional area (fCSA)], which disappeared with detraining and was recovered with retraining regardless of diet, pointing to a glycolytic-to-oxidative fiber shift. Transcriptomic analysis (bulk RNA-Seq) of the retrained muscle revealed a robust enhancement of mitochondrial oxidative phosphorylation (OxPhos) and mitoribosomal genes, paralleled by increases in OxPhos protein complex IV levels, higher long-chain fatty acid oxidative capacity [acyl-CoA dehydrogenase, long chain (ACADL)], and sustained citrate synthase activity 1 wk after retraining, reinforcing the optimization of mitochondrial metabolism. Although transcriptomic evidence revealed a major overlap between HFD- and CD-fed mice, discrepancies in protein abundance emerged, which point to an intricate regulation of mitochondrial programming that supports the muscle memory of growth. Our study identifies common and selective mechanisms by which the muscle memory of exercise overrides dietary challenges and promotes fiber hypertrophy, offering insight into potential mechanisms to leverage to promote healthy aging.<b>NEW & NOTEWORTHY</b> Here we provide evidence that exercise memory in skeletal muscle fine-tunes mitochondrial metabolism to respond to dietary challenges and support muscle growth. Using physiological, RNA sequencing, and biochemical approaches, we show that exercise retraining optimizes mitochondrial metabolism to increase fatty acid oxidative capacity. These findings enhance our understanding of how prior exercise primes muscle for enhanced adaptations, offering insights into strategies to promote healthy aging.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1239-C1255"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential regulation of NHE3 expression in type 1 and type 2 diabetic intestine: impaired endosomal regulation of NHE3 expression in type 1 diabetes.","authors":"Varsha Singh, Ruxian Lin, Laxmi Sunuwar, Jianbo Yang, Mark Donowitz, Rafiquel Sarker","doi":"10.1152/ajpcell.00590.2025","DOIUrl":"10.1152/ajpcell.00590.2025","url":null,"abstract":"<p><p>Chronic diarrhea is a frequent gastrointestinal complication in both type 1 (T1D) and type 2 diabetes (T2D), although the underlying mechanisms differ: T1D is linked to autonomic neuropathy and disrupted transporter regulation, whereas T2D is often linked to medications and intestinal inflammation. Using streptozotocin-induced mouse models of T1D and T2D, we observed increased luminal fluid in the small intestine of both. Given the role of Na⁺/H⁺ exchanger 3 (NHE3) in fluid absorption and its loss in most diarrheal diseases, we examined the NHE3 expression across intestinal segments. In T1D, the NHE3 protein was significantly reduced in the duodenum and jejunum without changes in mRNA, suggesting posttranscriptional regulation. In contrast, T2D mice exhibited reduced NHE3 protein and mRNA, restricted to the proximal colon. To investigate molecular mechanisms underlying NHE3 loss in T1D, we evaluated endosomal scaffolding proteins involved in NHE3 trafficking. Although our previous work showed that the sorting nexin-27 (SNX27)-retromer complex does not regulate NHE3 protein stability, we found that SNX17 was significantly decreased in the small intestine of T1D mice but unchanged in T2D. SNX17 knockdown in SK-CO15 cells reduced NHE3 activity and stability. A Glutathione S-Transferase (GST) pull-down assay showed that SNX17 interacts with the C-terminus of NHE3. Mutation of the NHE3 distal NPxY motif disrupted this interaction, leading to reduced NHE3 expression and increased degradation. These findings reveal segment-specific and mechanistically distinct causes of diabetic diarrhea in T1D versus T2D and identify SNX17 loss as a contributor to reduced NHE3 stability and activity in T1D, likely promoting diabetic diarrhea.<b>NEW & NOTEWORTHY</b> This study identifies distinct mechanisms of impaired sodium absorption contributing to diabetic diarrhea in type 1 and type 2 diabetes. We identify SNX17 as a novel regulator of NHE3 in the small intestine, showing that SNX17 loss in T1D contributes to posttranslational NHE3 destabilization. In contrast, T2D-associated NHE3 downregulation is transcriptional and confined to the colon. These findings reveal region-specific mechanisms of fluid malabsorption in diabetes, with direct implications for the development of targeted therapies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1256-C1267"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aquaporin 5 expression regulates MDA-MB-231 spheroid multicellular invasion.","authors":"Ian M Smith, Autumn C Hengen, Ariel W Abraham, Sai Pranav Majeti Venkata, Shohini Banerjee, Nikka Givpoor, Allison K Moses, Kimberly M Stroka","doi":"10.1152/ajpcell.00408.2025","DOIUrl":"10.1152/ajpcell.00408.2025","url":null,"abstract":"<p><p>Aquaporins are water transport proteins that regulate prometastatic behaviors in cancer, including cell invasion, proliferation, and epithelial-to-mesenchymal transition. Aquaporin 5, an isoform virtually absent from healthy tissues, is overexpressed in numerous cancer types. Studies have connected aquaporin 5 to the migratory and invasive properties of single cells in two-dimensional assays; however, the role of aquaporin 5 in inducing invasive phenotypes in models that recapitulate the tumor microenvironment remains unknown. To address this gap, MDA-MB-231 cell lines were created with aquaporin 5 overexpression and knockdown to identify the resulting single and collective cell motility in three-dimensional models. Upon validating the developed cell lines, aquaporin 5 expression regulated cell motility and invasion in varied biaxial microenvironments. In addition, aquaporin 5 was found to play a unique role in regulating MDA-MB-231 spheroid development, influencing the formation, size, circularity, and adhesion, distinct from its function in two-dimensional models. Finally, increased aquaporin 5 expression intensified the invasive capacity of spheroid multicellular protrusions by polarizing to their invasive front. In summary, this work expands upon the knowledge that aquaporin 5 enhances cell motility, while elucidating the previously unreported adhesive and multicellular invasive effects of aquaporin 5 in a three-dimensional model.<b>NEW & NOTEWORTHY</b> We identify a role for aquaporin 5 (AQP5) in multicellular spheroid invasion-a collective behavior distinct from two-dimensional (2D) migration and implicated in cancer progression. Elevated AQP5 expression increased spheroid cohesion alongside increased cell-cell adhesion proteins, contrasting with earlier observations that AQP5 disrupts cell-cell junctions in 2D. These findings reveal that AQP5 regulates invasion through context-dependent mechanisms in three-dimensional (3D) environments, highlighting the importance of studying AQP5 in models that capture the complexity of tumor architecture and collective cell dynamics.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1226-C1238"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabis improves metabolic dysfunction and macrophage signatures in obese mice.","authors":"Brandon N VanderVeen, Thomas D Cardaci, Christian A Unger, Mitchell M NeSmith, Jeffrey C Freeman, Arianna V Bastian, Kasie Roark, Mansi Upadhyay, Andrew G Levy, Brooke M Bullard, Sierra J McDonald, Kandy T Velázquez, Reilly T Enos, Jason L Kubinak, Lorne J Hofseth, James R Hebert, Daping Fan, E Angela Murphy","doi":"10.1152/ajpcell.00503.2025","DOIUrl":"10.1152/ajpcell.00503.2025","url":null,"abstract":"<p><p>Obesity rates continue to rise, highlighting the need for new treatments that are effective, safe, and widely accessible. Aligned with the easing of restrictions on cannabis use, interest in its therapeutic potential is evolving. As such, we examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ⁹-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Briefly, female C57BL/6 mice were randomized into four groups (<i>n</i> = 15/group): <i>1</i>) lean, <i>2</i>) obese placebo, <i>3</i>) obese CBD, and <i>4</i>) obese THC. Lean mice consumed a low-fat diet for the study duration. Obese mice consumed a high-fat diet for 16 wk before a 4-wk cannabis (3 times/wk; high CBD = ∼4.2 mg/kg and high THC = ∼7.3 mg/kg) intervention. Consistent with our hypothesis, obesity increased homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH), both of which were significantly mitigated by either high (10.5%) CBD or high (18.16%) THC cannabis (<i>P</i> < 0.05). Interestingly, these changes appeared to occur independent of significant weight loss or measurable changes in food intake. Diet-induced obesity also increased infiltrating macrophages, pan macrophages, and M1-like proinflammatory macrophages in adipose tissue and liver. These effects were rescued by high CBD and high THC (<i>P</i> < 0.05), providing evidence consistent with causation for the improvements in HOMA-IR and MASH. Despite the legal complexities surrounding cannabis use, these data suggest that both CBD and THC can be a viable therapy to target macrophages and improve metabolic health and immune dysregulation with obesity.<b>NEW & NOTEWORTHY</b> We examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ⁹-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Both CBD and THC mitigated the obesity-induced increase in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH). Furthermore, the increase in macrophages, in particular M1-like proinflammatory macrophages, in the adipose tissue and liver was rescued by high CBD and high THC.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1316-C1331"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ca²⁺ signal dynamics in maturing ureteric bud (UB) and collecting duct (CD) derived organoid tubules.","authors":"Rolando Carrisoza-Gaytán, Abigail Daily, Kayla J Wolf, Samia Lasaad, Anna Cantalupo, Pooja Nair, Ronald Van Gaal, Per Uhlén, Jennifer A Lewis, Lisa M Satlin","doi":"10.1152/ajpcell.00578.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00578.2025","url":null,"abstract":"<p><p>Mechanical signals sensed by human stem cells are transduced via discrete signaling pathways to modulate developmental phenotype and function. Proximal tubules isolated from nephron lineage-derived kidney organoids undergo a developmental increase in abundance and/or activity of the basolateral mechanosensor PIEZO1 and Ca²⁺ signal transduction pathways (Carrisoza-Gaytán et al. <i>AJP Cell Physiol</i>, 2023). Here, we investigate whether human iPSC-derived ureteric bud (UB) and collecting duct (CD) organoid cells exhibit a similar developmental increase in PIEZO1 function. Comparison of cells in tubules microdissected from UB and CD organoids cultured for 34-35 days (d) or 62-65 d showed an: (i) increased [Ca²⁺]_i response to basolateral application of the selective PIEZO1 agonist Yoda1 and (ii) decreased time to peak [Ca²⁺]_i with advancing days in culture. Single cell analyses of the Yoda1-induced [Ca²⁺]_i response revealed 7-15 mHz [Ca²⁺]_i oscillations that were more prevalent with advancing days in culture and differentiation (CD vs. UB). Concurrent exposure to inhibitors of the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) or the plasma membrane Ca²⁺-ATPase (PMCA) dampened the amplitude of the Yoda1-induced [Ca²⁺]_i oscillations. Bulk RNA analysis and pathway enrichment analysis revealed broad changes in genes associated with Ca²⁺ signaling, but not <i>PIEZO1</i>, with advancing days in culture and differentiation. These findings are consistent with a developmental increase in activity of PIEZO1 channels and/or maturation of associated pathways shaping Ca²⁺ signaling dynamics in maturing UB and CD organoids. Decoding of [Ca²⁺]_i oscillations may identify molecular mechanisms important in morphologic and functional differentiation of organoid tubules.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protection of the human aortic valve interstitial cells against radiation-induced remodeling by repression of the TRPM4 channel.","authors":"Margaux Aize, Laura Brard, Corentin Kerevel, Arthur Boilève, Harlyne Mpweme Bangando, Maysan Touihar, Benoit D Roussel, Alexandre Lebrun, Vladimir Saplacan, Alain Manrique, Christophe Simard, Romain Guinamard","doi":"10.1152/ajpcell.00535.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00535.2025","url":null,"abstract":"<p><p>Radiation-induced aortic valve deleterious remodeling may occur years after radiotherapy. The TRPM4 cation channel participates in aortic valve radiation-induced remodeling in mice <i>in vivo</i>. Valvular interstitial cells (VIC) are involved in valve leaflet thickening and calcification leading to aortic stenosis. TRPM4 favors their remodeling toward an osteogenic phenotype <i>in vitro</i>. Here, we evaluated whether radiation-induced remodeling involves TRPM4 in human VICs.</p><p><strong>Methods: </strong>VICs were isolated from aortic valves and maintained in procalcifying media supplemented or not with 9-phenanthrol (a TRPM4 inhibitor) or shRNA-TRPM4. Cells were irradiated at 0 or 8 Gy. 10 days post-irradiation, cell surface, viability, cycle and proliferation were measured. Senescence was evaluated by β-galactosidase activity measurements. Osteogenic markers (BMP2, Runx2, ALP) and TRPM4 mRNA levels were quantified by qPCR.</p><p><strong>Results: </strong>VIC surface increased after radiation while cell density decreased. Radiation had no effect on viability but induced an increase of the proportion of cells in G0 cell cycle phase. An increase of cell senescence was observed after irradiation. Finally, irradiation induced an increase of TRPM4, BMP2, Runx2 and ALP mRNA. All these effects were partly prevented by 9-phenanthrol or shRNA-TRPM4. Interestingly, VIC density on aortic valve leaflets from mice submitted to X ray treatment <i>in vivo</i> was decreased in treated animals compared to untreated ones and this was not observed in animals with disruption of the <i>Trpm4</i> gene.</p><p><strong>Conclusion: </strong>TRPM4 participates in radiation-induced hVICs remodeling by promoting cell senescence and osteogenic transition. TRPM4 may thus be evaluated as a therapeutic target to diminish valvular effects of radiotherapy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin-hemichannels-mediated ATP release causes lung injury following chlorine inhalation.","authors":"Ahmed Lazrak, Zhihong Yu, Sadis Matalon","doi":"10.1152/ajpcell.00397.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00397.2025","url":null,"abstract":"<p><p>Chlorine (Cl₂) is a highly reactive halogen gas that undergoes rapid hydrolysis in lung epithelial lining fluid (ELF) upon inhalation, forming hypochlorous acid (HOCl) and hydrochloric acid (HCl). These products subsequently, through chemical reactions, modify the structure and the function of membrane proteins. Herein, we investigated the effects of Cl₂ on connexin-hemichannels and the release of ATP in the ELF. Adult C57BL/6 mice were subjected to 400 ppm Cl₂ for 30 minutes. Subsequent analysis revealed a marked increase in ATP levels within the BAL, with concentrations reaching 43.952 ± 9.553 nM at 2 hours and 30.554 ± 7.383 nM at 24 hours post-exposure, relative to control. Additionally, at 24 hours post-exposure, the lung wet/dry (W/D) ratio significantly increased from 4.48 ± 0.142 to 5.067± 0.359, while alveolar fluid clearance (AFC) decreased from 0.249 ± 0.019 to 0.145 ± 0.018. Electrophysiological recordings in alveolar type 2 (AT2) cells revealed reduced open probabilities (P_o) of both ENaC (4 pS) and a cation channel (18 pS), declining from 0.323 ± 0.021 and 0.202 ± 0.022 to 0.151 ± 0.042 and 0.091 ± 0.019, respectively. Instillation of 50 μl of 100 μg/ml Gap27-a connexin mimetic peptide selectively inhibiting connexin-hemichannels-administered 30 minutes post-exposure, restored ATP to control, normalized the W/D ratio, improved AFC, and reestablished ENaC function. Moreover, Gap27 normalized airway resistance following methacholine challenge. In human airway smooth muscle cells (hASMCs), 100 μM ATP induced Ca_i²⁺ elevation and depolarized V_m to -40 mV, with both effects partially reversed by P2X₇R inhibitor, A804598.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autonomic Dysregulation and Atrial Arrhythmias.","authors":"Aleksei Mikhailov, Rishi Arora, Anna Pfenniger","doi":"10.1152/ajpcell.00537.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00537.2025","url":null,"abstract":"<p><p>The autonomic nervous system (ANS) and its dysregulation are recognized as important mechanisms underlying atrial arrhythmias, such as atrial fibrillation (AF). In this review, we describe the anatomy of the cardiac nervous system, sympathetic and parasympathetic effects on atrial electrophysiology, and how dysregulation of those may predispose to AF initiation and promote its maintenance. We then discuss how the ANS itself undergoes functional and structural remodeling in the setting of atrial arrhythmias, and what are the current neuromodulation approaches for AF prevention and treatment. These strategies include destruction of cardiac ANS structures or modification of autonomic signaling using nerve stimulation, pharmacological or gene therapy. Autonomic mechanisms of AF have been a focus of basic and translational research for many years, and now with the development of new diagnostic tools and therapeutic methods, ANS-targeted approaches have a potential to become an important part of AF treatment.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting microRNA-132 protects against kidney fibrosis and restricts myofibroblast differentiation from cells of renin lineage.","authors":"Loïs A K van der Pluijm, Angela Koudijs, Jacques Mgj Duijs, Wendy Stam, Joris I Rotmans, Anton Jan van Zonneveld, Roel Bijkerk","doi":"10.1152/ajpcell.00427.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00427.2025","url":null,"abstract":"<p><p>Kidney fibrosis represents a central pathophysiological process in the progression of chronic kidney disease to end-stage kidney failure, yet its underlying cellular mechanisms remain incompletely understood. Cells of renin lineage (CoRL) have been shown to possess regenerative capacity following injury, but may also contribute to fibrotic remodeling. MicroRNA-132 (miR-132), known to regulate both fibrotic signaling and renin synthesis, represents a potential therapeutic target to halt progression of kidney fibrosis. Here, we investigated the role of miR-132 and CoRL in two complementary models of kidney injury-5/6 nephrectomy (5/6NX) and bilateral ischemia-reperfusion injury (bIRI)-using renin lineage-tracing mice treated with a miR-132 antimiR or scrambled control. In both models, miR-132 silencing improved renal function and led to a consistent reduction in interstitial fibrosis and myofibroblast accumulation in the kidney. The number of proliferating myofibroblasts also declined, supporting an antiproliferative effect. Podocyte number per glomerulus was significantly higher upon miR-132 silencing, indicating protection from glomerular damage. CoRL-derived podocytes were present in both models, but not affected by miR-132 knockdown, suggesting that the observed podocyte protection primarily results from reduced loss of resident cells. Lineage tracing further confirmed that CoRL contribute directly to the pool of αSMA+ myofibroblasts. Interestingly, miR-132 silencing reduced the number of CoRL-derived myofibroblasts. Together, these findings identify miR-132 as a regulator of fibrotic remodeling and highlight the dual regenerative and fibrogenic potential of CoRL. Pharmacological inhibition of miR-132 may offer a promising approach to preserve kidney function and limiting fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the molecular cargos associated with extracellular vesicles extracted from bone tissue to identify novel players in osteoblast function.","authors":"Floriane Binet, Laura Entz, Meggane Amiot, Solène Tessier, Joëlle Véziers, Laurence De Beaurepaire, Gwennan André-Grégoire, Florent Dingli, Damarys Loew, Pierre Weiss, Angélique Galvani, Valérie Geoffroy","doi":"10.1152/ajpcell.00272.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00272.2025","url":null,"abstract":"<p><p>Extracellular vesicles (EVs), composed of proteins, lipids, and nucleic acids, are key mediators of intercellular communication across various tissues. However, research on EVs isolated directly from bone tissue remains limited. Here we identified for the first time and characterized two EV subpopulations extracted from bone tissue and enhanced our understanding of their roles in bone physiology. These two EV subpopulations were reproducibly isolated, a large EV population (lEV; 237.7 ± 8.8 nm) and a small EV population (sEV; 109.2 ± 8.3 nm), both exhibiting the expected shape and presence of EV and bone cell markers. Comparative analysis of their cargos revealed unique or enriched proteins and miRNAs profile for each, suggesting shared functional characteristics with bone cells, including osteocytes, osteoblasts, and osteoclasts. Notably, lEVs contained proteins such as FHL2 and pleiotrophin, along with miRNAs including miR-15b-5p, miR-29a-3p, and miR-128-3p, all of which are involved in early osteogenic signaling pathways such as Hippo, TGF-β, and Wnt. Furthermore, sEVs contained ALP, PAPSS2 and miR-125b, both known regulators of matrix mineralization. Both EV subpopulations were internalized by stromal ST2 and pre-osteoblastic MC3T3-E1 cells. We present evidence that lEVs significantly enhanced ALP activity in ST2 cells, indicating early osteogenic stimulation, while sEVs partially promoted matrix mineralization in primary osteoblasts. Our findings provide novel insights into the role of bone-derived EVs as possible complementary mediators of osteogenesis <i>in vivo</i> and highlight the potential of their cargos in advancing bone regeneration strategies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}