American journal of physiology. Cell physiology最新文献

{"title":"Loss of α7 nicotinic acetylcholine receptor exacerbates adrenergic-induced cardiac damage.","authors":"Kiany Miranda, Vanessa Pereira Teixeira, Sérgio A Scalzo, Lígia Reis de Moura Estevão, Anderson Kenedy Santos, Bruno Sanches, Marcos Eliezeck, Fernando A Espanhol, Henrique Abramo, Lucas M Kangussu, Lucíola S Barcelos, Vânia Prado, Marco A M Prado, Cibele Rocha-Resende, Silvia Guatimosim","doi":"10.1152/ajpcell.00839.2025","DOIUrl":"10.1152/ajpcell.00839.2025","url":null,"abstract":"<p><p>Previous studies have implicated the α7 nicotinic acetylcholine receptor (α7nAChR) in cardioprotection via its anti-inflammatory effects, yet the underlying mechanisms remain poorly understood. Here, we investigated the impact of α7nAChR deficiency on cardiac injury induced by a 7-day isoproterenol (ISO) treatment in littermate wild-type (WT) and α7nAChR-knockout (α7-KO) mice. ISO administration in WT mice led to a marked upregulation of α7nAChR expression in cardiac tissue and isolated cardiomyocytes, suggesting a compensatory response to adrenergic stress. To investigate this hypothesis, we assessed ISO-induced structural and inflammatory changes in both genotypes. ISO-treated WT mice developed isolated cardiac hypertrophy with minimal inflammation or fibrosis. In contrast, α7-KO mice subjected to ISO treatment displayed exacerbated hypertrophy and fibrosis. These alterations were accompanied by marked leukocyte accumulation, supporting the anti-inflammatory role of α7nAChR. To explore this further, we characterized the inflammatory profile using flow cytometry. FACS-analyzed hearts from α7-KO/ISO mice exhibited increased monocyte infiltration and a marked expansion of the CCR2⁺ population compared with WT/ISO. This phenotype was associated with greater cardiomyocyte death. In vitro, isolated ventricular myocytes lacking α7nAChR were intrinsically more susceptible to ISO-induced cytotoxicity, indicating that α7nAChR exerts a cell-autonomous protective role beyond its anti-inflammatory function. Our findings establish α7nAChR as a key determinant of cardiac resilience to adrenergic insult and underscore its potential as a therapeutic target for mitigating myocardial injury.<b>NEW & NOTEWORTHY</b> Although α7nAChR has been implicated in cardioprotection through its anti-inflammatory properties, the mechanisms underlying these effects remain elusive. We demonstrate that α7nAChR deficiency heightens susceptibility to adrenergic-induced injury, characterized by enhanced cardiomyocyte death and monocyte infiltration. Our findings confirm the anti-inflammatory role of α7nAChR and reveal its cell-autonomous prosurvival effects on cardiomyocytes, broadening our understanding of mechanisms driving cholinergic cardioprotection. This work positions α7nAChR as a regulator of myocardial resilience and highlights its therapeutic potential.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C706-C714"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951284","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 activated kidney fibroblasts via ferroptosis: a potential antifibrotic strategy.","authors":"Inga Sörensen-Zender, Rong Song, Julius Sinning, Tamar Kapanadze, Kai M Schmidt-Ott, Anette Melk, Roland Schmitt","doi":"10.1152/ajpcell.00660.2025","DOIUrl":"10.1152/ajpcell.00660.2025","url":null,"abstract":"<p><p>Kidney fibrosis is characterized by excessive deposition of extracellular matrix, which is ultimately disrupting normal renal architecture. Despite its clinical relevance, no targeted antifibrotic therapies are currently available. Myofibroblasts, primarily derived from pericytes and resident fibroblasts, are key effectors of fibrosis due to their high extracellular matrix production. Here, we tested the hypothesis that ferroptosis induction would enable the targeted elimination of activated kidney fibroblasts. We found that kidney fibroblasts exhibit marked sensitivity to ferroptotic cell death upon exposure to the ferroptosis inducer RAS-selective lethal 3 (RSL3), an effect further amplified by transforming growth factor-β stimulation. In tissue slice cultures of murine fibrotic kidneys, RSL3 eliminated myofibroblasts without causing overt damage to other cell types. Extending these findings in vivo, we applied a postischemia/reperfusion model of kidney fibrosis and demonstrated that repeated low-dose systemic administration of RSL3 significantly reduced the activated fibroblast population without inducing appreciable injury to parenchymal cells. These results provide proof-of-principle that the ferroptosis susceptibility of activated fibroblasts may offer a potential strategy for the selective depletion of profibrotic effector cells in kidney fibrosis.<b>NEW & NOTEWORTHY</b> This study reveals ferroptosis, a pharmacologically inducible form of cell death, as a novel mechanism to eliminate activated fibroblasts, the main drivers of kidney fibrosis. Due to their high ferroptosis sensitivity, these cells are selectively depleted by RSL3 in vitro, in kidney tissue slice cultures, and in fibrotic kidneys in vivo. These findings highlight ferroptosis induction as a promising antifibrotic strategy in kidney disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C619-C627"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964967","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":"The angiotensin II receptor antagonist telmisartan promotes renal recovery after ischemia-reperfusion injury by reprogramming fatty acid metabolism.","authors":"Chang Chu, Denis Delić, Zeyu Zhang, Shufei Zeng, Mohamed M S Gaballa, Thomas Klein, Saban Elitok, Carl-Friedrich Hocher, Bernhard K Krämer, Xin Chen, Berthold Hocher","doi":"10.1152/ajpcell.00801.2025","DOIUrl":"10.1152/ajpcell.00801.2025","url":null,"abstract":"<p><p>Current clinical guidelines recommend withholding renin-angiotensin-aldosterone system (RAAS) inhibitors during acute kidney injury (AKI) due to concerns over impaired glomerular perfusion. However, their potential to mitigate post-AKI inflammation and fibrosis remains unexplored. We hypothesized that telmisartan, an angiotensin II receptor blocker (ARB) with reported peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, would enhance recovery from ischemic AKI. Male Wistar rats were subjected to unilateral nephrectomy and 45-min ischemia in the contralateral kidney, or sham surgery. Animals were randomized to receive telmisartan (3 mg/kg/day) or placebo for 10 days, starting 1 wk before injury. Telmisartan treatment significantly accelerated the recovery of renal function and attenuated tubular necrosis, inflammation, and the expression of injury biomarkers. At the whole kidney tissue level at 72 h postischemia-reperfusion injury (IRI), bulk RNA-sequencing compared with healthy control mice without IRI revealed apparent broad metabolic dysfunction, with suppression of fatty acid oxidation and mitochondrial pathways, which may reflect both injury-driven changes in cellular composition and transcriptional regulation within surviving cells. These transcriptomic findings 72 h after IRI were significantly blunted or even abolished by telmisartan. These treatment effects did not show evidence of direct PPAR-γ pathway activation. This study suggests that the metabolic modulatory effects of certain angiotensin II receptor blockers may provide therapeutic benefit during the recovery phase of AKI, independent of direct PPAR-γ signaling.<b>NEW & NOTEWORTHY</b> RAAS inhibitors are routinely withheld during acute kidney injury (AKI) because of concerns about impaired renal perfusion. Contrary to this dogma, we show that telmisartan enhances renal recovery following ischemia-reperfusion injury. Transcriptomic analyses reveal that telmisartan restores fatty acid oxidation and mitochondrial-peroxisomal lipid metabolism, key pathways suppressed in AKI. These findings suggest that selected RAAS inhibitors may actively promote post-AKI metabolic recovery rather than merely pose hemodynamic risk.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C695-C705"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123477","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":"Microglia alter autonomic nucleus neuronal activation after peripheral cytokine challenge.","authors":"Emily A Castellanos, Luke A Schwerdtfeger, Bret N Smith, Stuart A Tobet","doi":"10.1152/ajpcell.00810.2025","DOIUrl":"10.1152/ajpcell.00810.2025","url":null,"abstract":"<p><p>The autonomic nervous system (ANS) coordinates the body's response to stress. Proinflammatory cytokines [e.g., tumor necrosis factor-alpha (TNFα)], released in response to different stressors, may influence underlying pathophysiology involving autonomic dysfunction. The present study evaluated the impact of peripheral TNFα on cellular activation in brain stem nuclei associated with autonomic function, including the dorsal vagal complex (DVC) and the ventral lateral medulla (VLM). Mice received a single intraperitoneal injection of TNFα and were processed 2 h later to identify immunoreactive c-Fos in brain stem nuclei as a measure of cellular activity. The number of c-Fos-immunoreactive cells increased after TNFα challenge within the DVC and VLM. Cells immunoreactive for c-Fos were concentrated lateral to the area postrema (AP), a circumventricular organ medial to the subdivision of the caudal portion of the nucleus of the solitary tract (cNTS) within the DVC. To examine the role of microglia in mediating cellular responses to peripheral TNFα, minocycline was administered into the fourth ventricle to decrease microglial function. Minocycline treatment reduced ionized calcium binding adapter molecule 1 (IBA-1) immunoreactivity in the AP and cNTS. When animals were challenged with TNFα after receiving minocycline, fewer c-Fos-positive cells were induced in the DVC and selectively in the rostral VLM. These findings highlight the spatial selectivity of cells in the brain stem to increased peripheral proinflammatory signaling, as well as the impact of resident microglia on autonomic circuitry responses.<b>NEW & NOTEWORTHY</b> This study investigates how peripheral tumor necrosis factor-alpha (TNFα) affects neuronal activity in autonomic nuclei of the brain stem and how microglia contribute to this response. Peripheral TNFα increased neuronal activation (c-Fos expression) in the dorsal vagal complex (DVC) and ventrolateral medulla (VLM), particularly near the area postrema. Inhibiting microglia with intracerebroventricular minocycline reduced both microglial markers and TNFα-induced neuronal activity, suggesting that microglia play a key role in modulating cytokine-driven autonomic signaling in the brain stem.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C683-C694"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12961895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140811","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":"Central activation of chaperone-mediated autophagy reduces appetite by fine-tuning hypothalamic amino acid pools: new insights from fish.","authors":"Steffi Reji, Emilio J Vélez, Ayelén M Blanco, Cecile Heraud, Vincent Véron, Karine Dias, Alexandre Stella, Odile Burlet-Schiltz, Simon Schnebert, Jérôme Roy, Florian Beaumatin, Beth Cleveland, José L Soengas, Iban Seiliez","doi":"10.1152/ajpcell.00765.2025","DOIUrl":"10.1152/ajpcell.00765.2025","url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA) is a key lysosomal proteolytic pathway essential for cellular homeostasis and metabolism, with dysfunction linked to various human diseases. Although extensively studied in humans and mice, CMA was only recently identified in fish, paving the way for novel and evolutionary research perspectives. Here, we demonstrate a role for CMA in regulating feed intake (FI) in rainbow trout (<i>Oncorhynchus mykiss</i>), a major aquaculture species and a widely used model in numerous research fields, including physiology, evolutionary genetics, toxicology, immunology, and nutrition. Specifically, we observed that feed deprivation induces an increase in the CMA activation score-a reliable proxy for CMA activity-in the hypothalamus, a central brain region involved in the regulation of feeding behavior. To probe its functional relevance, we intracerebroventricularly (ICV) injected the CMA activator CA77.1 and found a significant reduction in FI levels, suggesting a regulatory role for CMA in appetite. Further analysis suggested that CMA may regulate FI partly through changes in hypothalamic free amino acid availability, with ribosomal protein degradation potentially contributing to this mechanism. Through this mechanism, CMA may play a critical role in the precise regulation of satiety and also represent a promising target for therapeutic strategies aimed at treating metabolic disorders, as well as for nutritional interventions to improve feed efficiency and promote more sustainable growth practices in aquaculture.<b>NEW & NOTEWORTHY</b> This study shows in vivo, in a nonmammalian vertebrate, that chaperone-mediated autophagy (CMA) regulates appetite. It demonstrates that hypothalamic CMA activity increases during feed deprivation and that pharmacological activation of CMA suppresses feed intake by locally modulating amino acid availability. These findings reveal a previously uncharacterized link between CMA, hypothalamic amino acid pools, and appetite regulation, and suggest a novel intracellular mechanism linking proteostasis to nutrient sensing and feeding behavior in vertebrates.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C590-C604"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951215","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":"The cardiac neurovascular unit: sympathetic control of the capillary network in aging and transplantation.","authors":"Laura Poli, Camilla Olianti, Maria Gemma Pignataro, Anna Di Bona, Leonardo Sacconi, Giulia d'Amati, Marco Mongillo, Tania Zaglia","doi":"10.1152/ajpcell.00841.2025","DOIUrl":"10.1152/ajpcell.00841.2025","url":null,"abstract":"<p><p>Sympathetic nerves are key regulators of cardiac performance, yet their micro-anatomical relationship with the coronary microcirculation remains incompletely defined. Here, we identify a previously underappreciated cardiac NeuroVascular Unit (NVU), in which sympathetic fibers frequently lie in close anatomical apposition to capillary endothelial cells. Using confocal and ultrastructural imaging in mouse and human hearts, we demonstrate that a substantial fraction of tyrosine hydroxylase-positive processes aligns with the capillary network, suggesting a structural framework for local neurovascular communication. Cardiac aging was associated with fragmentation and rarefaction of sympathetic fibers, accompanied by cardiomyocyte atrophy and capillary remodeling characterized by increased vessel density and reduced caliber. Pharmacological sympathectomy in young mice reproduced these changes, establishing a causal link between sympathetic integrity, cardiomyocyte trophism, and microvascular organization. Control experiments excluded direct vascular toxicity of 6-hydroxydopamine, and combined adrenalectomy-sympathectomy confirmed that these effects were independent of circulating catecholamines. Analysis of transplanted human hearts, an established clinical model of abrupt cardiac denervation, revealed an early-established and persistent reduction in capillary diameter compared with controls, mirroring the phenotype observed in mice. Together, these findings define the cardiac NVU as a structural neurovascular interface integrating sympathetic, endothelial, and myocyte compartments, with potential functional implications. Recognition of this neurovascular architecture revises current paradigms of cardiac autonomic regulation and suggests new avenues for targeting microvascular-neuronal apposition in cardiac aging and transplantation.<b>NEW & NOTEWORTHY</b> This study identifies a previously unrecognized cardiac neurovascular unit in which sympathetic fibers lie in close anatomical apposition to capillary endothelial cells. Disruption of this cell-to-cell interface, during aging, pharmacological sympathectomy, or following heart transplantation, is associated with capillary remodeling and cardiomyocyte atrophy. These findings broaden current concepts of cardiac autonomic regulation and highlight the coronary microcirculation as a structural component shaped by sympathetic integrity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C669-C682"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083905","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":"Have we been overlooking K channels in the era of CFTR modulators?","authors":"Frédéric Becq","doi":"10.1152/ajpcell.00908.2025","DOIUrl":"10.1152/ajpcell.00908.2025","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C628-C630"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016923","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":"Acute ketone monoester ingestion increases monocyte lysine β-hydroxybutyrylation and plasma β-hydroxybutyrate amino acid conjugates in humans.","authors":"Alexis Marcotte-Chénard, Roderick E Sandilands, Alexandre Abílio Teixeira, Seth F McCarthy, Maria Dolores Moya-Garzon, Emily Goldberg, Jonathan Z Long, Hashim Islam, Jonathan P Little","doi":"10.1152/ajpcell.00896.2025","DOIUrl":"10.1152/ajpcell.00896.2025","url":null,"abstract":"<p><p>Endogenous ketosis during fasting can induce β-hydroxybutyrylation of lysine residues on proteins (known as Kbhb) in human immune cells and increase circulating β-hydroxybutyrate (BHB) amino acid conjugates, both of which are hypothesized to have functional physiological consequences. It remains unknown if similar modifications occur with acute consumption of an exogenous ketone monoester (KME) supplement [(<i>R</i>)-3-hydroxybutyl (<i>R</i>)-3-hydroxybutyrate], which robustly increases circulating BHB. Thirteen healthy adults (7 females; 6 males, age: 28 ± 7 yr) consumed 0.750 g/kg body mass KME with blood samples collected before and after 2 h, coinciding with peak plasma BHB concentration. Monocytes (CD14⁺) were isolated by negative immunomagnetic selection for Kbhb assessment by immunoblotting. Plasma BHB-amino acid conjugates were quantified by mass spectrometry. Blood BHB concentration significantly increased after KME consumption (<i>P</i> < 0.0001), peaking at 2 h (5.0 ± 0.8 mmol/L). Compared with baseline, monocyte Kbhb was significantly increased after 2 h (∼70% increase; <i>P</i> = 0.004). Plasma BHB-amino acid conjugates, including BHB-phenylalanine, -leucine, -valine, and -methionine were also increased at 2 h (<i>P</i> < 0.0001). Changes in capillary blood BHB and BHB-amino acid concentrations were positively correlated (<i>r</i> ≥ 0.58; <i>P</i> ≤ 0.046), suggesting a dose-dependent increase. Acute high-dose KME ingestion increases monocyte lysine Kbhb and plasma BHB amino acid conjugates in healthy humans, highlighting the possible immunomodulatory and systemic signaling effects of raising BHB through exogenous ketone supplementation.<b>NEW & NOTEWORTHY</b> This study provides the first in vivo evidence that exogenous ketone supplementation elevates lysine Kbhb in monocytes of healthy humans. Exogenous ketone supplementation also increased recently discovered BHB-amino acid conjugates, including BHB-phenylalanine, -leucine, -valine, and -methionine. These results highlight the potential immunomodulatory and systemic signaling effects of exogenous ketones.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"330 3","pages":"C643-C650"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218358","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":"GPR39 activation inhibits AQP2 trafficking and alters cytoskeletal organization.","authors":"Mackenzie K Kui, Jessica J Zhang, Ibrahim A Ahmed, Shishir Kumar Patel, Tara Fallah Rastegar, Hamid Rabb, Jennifer L Pluznick","doi":"10.1152/ajpcell.00748.2025","DOIUrl":"10.1152/ajpcell.00748.2025","url":null,"abstract":"<p><p>G protein-coupled receptor 39 (GPR39) is an orphan receptor that is highly expressed in renal collecting duct principal cells. GPR39 activation in vivo leads to reduced urinary concentration capacity. In this study, we used mpkCCD cells, a model of principal cells in the collecting duct, to examine the cell biological effects of GPR39 activation. Pharmacological activation of GPR39 with the synthetic agonist cpd1324 impaired vasopressin-mediated aquaporin-2 (AQP2) apical trafficking and reduced total AQP2 expression following long-term treatment, consistent with its known in vivo role. These effects were absent in GPR39 knockout cells. In addition, GPR39 activation altered apical membrane morphology, disrupted the tight junction network, and reduced cortical F-actin expression, suggesting a shift toward a dedifferentiated phenotype. GPR39 activation also increased glycolytic ATP production while reducing mitochondrial ATP output without affecting proliferation. RNA-Seq analysis of acutely treated mpkCCD cells revealed upregulation of inflammatory and dedifferentiation-associated gene programs, including cytokines. These findings indicate that the role of GPR39 in principal cells goes beyond AQP2 regulation and imply that GPR39 functions as a negative regulator of epithelial differentiation, perhaps acting to coordinate metabolic and inflammatory responses to stress.<b>NEW & NOTEWORTHY</b> This study presents the first exploration of the cellular and molecular mechanisms underlying GPR39 activation in a physiologically relevant in vitro model of the renal collecting duct, mpkCCD cells. Our findings implicate GPR39 in the regulation of aquaporin-2 expression and trafficking, cytoskeletal organization, and cellular metabolism. In addition, RNA sequencing of GPR39-activated cells revealed transcriptomic changes related to immune signaling, stress response, and differentiation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C448-C459"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910022","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":"Plasma extracellular vesicle signatures of metabolic health and exercise response in a pilot study of older adults.","authors":"Xin Zhang, William E Kraus, Joseph A Houmard, Johanna L Johnson, Virginia Byers Kraus","doi":"10.1152/ajpcell.00816.2025","DOIUrl":"10.1152/ajpcell.00816.2025","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are key mediators of intercellular communication and regulators of cellular function, yet their roles in metabolic health and exercise response are poorly understood. This pilot study analyzed plasma from older adults (<i>n</i> = 20) in subgroups of the well-characterized Studies Targeting Risk Reduction Interventions through Defined Exercise (STRRIDE) study to evaluate plasma EV biomarkers as minimally invasive biomarkers of metabolic health and exercise responsiveness. Plasma EVs comprised highly heterogeneous subpopulations defined by diverse surface markers reflecting complex cellular origins. At baseline, multiple EV biomarkers related to immune cells, skeletal muscle, and mesenchymal stem cells were associated with better indices of insulin action, including nine EV subpopulations with lower fasting insulin concentration and eight with lower Homeostatic Model Assessment for Insulin Resistance. Low-amount (∼1,300 kcal/wk), vigorous-intensity (65%-80% peak oxygen consumption) aerobic exercise increased the FABP4⁺ EV subpopulation in older adults (<i>n</i> = 12). High-amount (∼2,200 kcal/wk), vigorous-intensity exercise increased 15 EV subpopulations in older adults (<i>n</i> = 8). These subpopulations arise from a variety of cell sources, including immune cells (primarily lymphoid cells), skeletal and cardiac muscle, erythroid cells, mesenchymal and hematopoietic stem cells. Notably, eight out of 15 high-amount exercise-induced EV subpopulations were insulin action-related (CD29⁺, CD8⁺, CD56⁺, CD19⁺, MCAD⁺, CD73⁺, CD105⁺, and CD235a⁺). The EV-based profiling platform established here is ready for validation in larger human exercise cohorts, including the full STRRIDE cohort.<b>NEW & NOTEWORTHY</b> Specific plasma EV biomarkers related to immune subsets, skeletal muscle, and mesenchymal stem cells were associated with better indices of insulin action at baseline. High-volume, vigorous-intensity aerobic exercise increased many of these insulin action-related EV subpopulations. We developed a novel, minimally invasive platform that uses plasma EV surface markers to assess metabolic health and exercise responsiveness. This platform is ready for validation in larger human cohorts, including the full STRRIDE cohort.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C379-C389"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12866931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145853081","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}