{"title":"Active salt transport and countercurrent exchange as the basis of urine concentration: a proposal grounded on the microanatomy of the renal medulla.","authors":"Wilhelm Kriz, Brigitte Kaissling, Michel Le Hir","doi":"10.1007/s00424-026-03152-5","DOIUrl":"10.1007/s00424-026-03152-5","url":null,"abstract":"<p><p>The longitudinal arrangement of tubules and vessels in the renal medulla has in the early fifties of the last century given birth to the concept of countercurrent multiplication (CCM). Since then, enormous research has been expended, but a consent on a common concept of the urinary concentrating mechanism has not been reached. Strictly based on the microanatomy of the renal medulla and the transport capacities of the involved tubules and vessels, we propose a mechanism, in which countercurrent exchange (CCE) operates at different levels in the outer and inner medulla to create gradients of salt and urea and to impede their dissipation. Salt release by ascending thick and thin loop limbs (TALs and ATLs) including the bend segments and urea release by terminal collecting ducts (CDs) increase at any medullary level solute concentrations in ascending vasa recta (AVRs) above those in descending loop limbs (DLs) and CDs leading to water extraction from both resulting in final urine concentration. Solute loss by washout is minimized by counter-current exchange between AVRs and descending vasa recta (DVRs), continuously balanced through addition of salt by ATLs and urea by terminal CDs.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 2","pages":"23"},"PeriodicalIF":3.2,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12904963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"With a little help from a friend - a new partner for acid-sensitive channels.","authors":"Jochen Roeper","doi":"10.1007/s00424-026-03154-3","DOIUrl":"10.1007/s00424-026-03154-3","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 2","pages":"22"},"PeriodicalIF":2.9,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12904871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Noah Brechmann, Tamara Büttner, Bernd Walkenfort, Buena Delos Reyes, Daniel Schäfer, Sebastian Schlücker, Dirk Mayer, Mike Hasenberg, Joachim Fandrey, Karsten Seidl, Sandra Winning
{"title":"Just a little prick: careful cell contacts enabled by ceramic nanostraws.","authors":"Noah Brechmann, Tamara Büttner, Bernd Walkenfort, Buena Delos Reyes, Daniel Schäfer, Sebastian Schlücker, Dirk Mayer, Mike Hasenberg, Joachim Fandrey, Karsten Seidl, Sandra Winning","doi":"10.1007/s00424-026-03150-7","DOIUrl":"10.1007/s00424-026-03150-7","url":null,"abstract":"<p><p>Nanostraw arrays represent a novel and promising approach for the controlled delivery of substances into cells characterized by very little cellular activation or damage. Herein, we describe a sensitive strategy to establish intracellular contact with human macrophage-like differentiated THP-1 cells. Macrophages must function under stressful in-vivo conditions in oxygen-deprived tissues with inflammation. THP-1 cells stayed healthy and did not show signs of activation when cultured on nanostraw arrays. Importantly, we found convincing evidence for the successful delivery of gold nanoparticles and fluorescence-labeled antibodies into THP-1 cells. Future applications of nanostraw arrays are the functionalization with silane coating to immobilize proteins and/or the analysis of membrane located ion channels in THP-1 cells by electrophysiology. Our findings demonstrate that nanostraw arrays can enable intracellular contact for substance delivery and they might also allow measurements of the cellular membrane potential under stressful culture conditions like hypoxia in the future, in particular for immune cells.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 2","pages":"21"},"PeriodicalIF":3.2,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Octávio A C Maia, Luiz M Oliveira, Jan-Marino Ramirez, Ana C Takakura, Thiago S Moreira
{"title":"Tachykinergic signaling mediated by NK1 receptors in the respiratory parafacial region drives respiratory output and contributes to the chemoreflex response to CO<sub>2</sub>.","authors":"Octávio A C Maia, Luiz M Oliveira, Jan-Marino Ramirez, Ana C Takakura, Thiago S Moreira","doi":"10.1007/s00424-025-03147-8","DOIUrl":"10.1007/s00424-025-03147-8","url":null,"abstract":"<p><p>The respiratory parafacial region (pFRG) contributes critically to central chemoreception, CO2/H+ homeostasis and the regulation of all major components of the respiratory rhythm. The respiratory rhythm is also modulated by the neuropeptide substance P which is released by tachykinin-1 (Tac1)- expressing neurons. However, how tachykinergic signaling modulates the pFRG region remains incompletely understood. Here we show that substance P (1 µM, 30 nL) microinjected into the ventral pFRG increased respiratory frequency, amplitude, and minute volume under baseline conditions. These excitatory effects were abolished by prior application of the NK1 receptor antagonist GR82334, confirming NK1-mediated effect. Bilateral blockade of NK1 receptors in the ventral pFRG significantly attenuated hypercapnia-induced (FiCO2= 0.07) increases in respiratory parameters, suggesting tachykinergic signaling in CO2 chemoreflex responses. Immunohistochemical analysis revealed a predominant co-localization of NK1 receptors with VGlut2-expressing glutamatergic neurons in the ventral pFRG, whereas minimal co-expression was found with GABAergic neurons. To directly assess the function of tachykinin-producing neurons, we optogenetically stimulated Tac1-expressing neurons in the ventral pFRG. Light activation produced immediate increases in respiratory rate and motor output. These findings demonstrate that tachykinin signaling in the ventral pFRG enhances respiratory output. Tac1-expressing neurons may function as an integrative hub for coordinating respiratory functions under baseline and chemoreflex conditions.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 2","pages":"20"},"PeriodicalIF":3.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rodrigo Zamora-Cárdenas, Ana Laura López-Serrano, Tania Ferrer, Javier Alamilla, Aldo A Rodríguez-Menchaca, Eloy G Moreno-Galindo, Ricardo A Navarro-Polanco
{"title":"The progression of triple-negative breast cancer is linked to a gradual decrease of the BK channel in the plasma membrane and an increase in intracellular structures.","authors":"Rodrigo Zamora-Cárdenas, Ana Laura López-Serrano, Tania Ferrer, Javier Alamilla, Aldo A Rodríguez-Menchaca, Eloy G Moreno-Galindo, Ricardo A Navarro-Polanco","doi":"10.1007/s00424-025-03133-0","DOIUrl":"10.1007/s00424-025-03133-0","url":null,"abstract":"<p><p>Big Potassium (BK) channels are gated by both the membrane potential and intracellular Ca<sup>2+,</sup> and hence they have multiple physiological roles, from canonical control of cellular excitability to modulate cell metabolism, proliferation, and gene expression. Growing evidence implicates BK channels in several oncogenic processes, including breast cancer. Though, the role of these channels in the deleterious triple-negative breast cancer (TNBC) is unknown. In this study, electrophysiological methods and immunocytochemistry were performed to assess the functional contribution of BK channels in the progression of TNBC, using cell lines of increasing tumor stages. Firstly, we unveiled that BK channel is the main contributor of K<sup>+</sup> outward current in non-tumoral mammary cells (MCF-10 A and MCF-12 A). Also, as the cancer stage increased, the BK current density decreased (which was consistent with the lower expression of BK protein in the plasma membrane), whereas the protein was overexpressed inside tumoral cells. Biological assays disclose that pharmacological inhibition of BK channels in non-tumoral and TNBC cells enhanced cell migration, proliferation, and viability. Overall, these channels appear to have opposite role at the plasma membrane and intracellularly, since both the reduction of BK channel activity at the plasma membrane (either by decreased expression or by paxilline blockade) and the increased intracellular expression of this protein favor TNBC malignancy. Our findings suggest that BK channels may have multiple physiological implications in TNBC, depending on their function and the cellular organelle in which they are expressed.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 2","pages":"19"},"PeriodicalIF":3.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Acid-Base homeostasis in the brain: regional heterogeneity and different Acid-Base transporters.","authors":"Masoumeh Kourosh-Arami, Alireza Komaki","doi":"10.1007/s00424-025-03148-7","DOIUrl":"10.1007/s00424-025-03148-7","url":null,"abstract":"<p><p>The brain employs a sophisticated and multi-layered system to maintain its delicate acid-base balance, ensuring optimal conditions for neuronal and glial function. This intricate regulation involves a combination of chemical buffering, active transport mechanisms, and systemic controls. The balance of pH in mammalian cells is vital for the control of metabolism, as hydrogen and hydroxyl ions are essential. It is important for the nervous system to keep its pH in a neutral range (7.2-7.6) for proper function. Even small pH changes can impact neuron activity, synaptic transmission, and communication between cells. Many membrane proteins sensitive to pH changes play vital roles in neurotransmission. Recent research has identified pH-sensitive proteins that respond to acidic (pH 5) and alkaline (pH 9) conditions, influencing various cellular activities. This review discusses these pH-sensitive proteins in neurons.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 1","pages":"18"},"PeriodicalIF":3.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lili Hong, Yi An, Xiaoyuan Feng, Huan Chen, Lei An, Guo Zhang
{"title":"Electroacupuncture as a therapeutic intervention for obesity: mechanisms and implications.","authors":"Lili Hong, Yi An, Xiaoyuan Feng, Huan Chen, Lei An, Guo Zhang","doi":"10.1007/s00424-025-03149-6","DOIUrl":"10.1007/s00424-025-03149-6","url":null,"abstract":"<p><p>Obesity, a prevalent metabolic disease characterized by chronic systemic inflammation and dysregulated energy homeostasis, contributes to comorbidities such as type 2 diabetes and non-alcoholic fatty liver disease. Despite advancements in lifestyle interventions, pharmacotherapy and bariatric surgery, limitations in efficacy and safety emphasize the necessity for alternative therapeutic interventions. Electroacupuncture (EA), a contemporary form of traditional acupuncture, has emerged as a promising non-invasive intervention for obesity. This review synthesizes current evidence on the neuroendocrine, immunomodulatory, and metabolic mechanisms through which EA modulates hypothalamic nuclei, gut-liver axis signaling, white adipose tissue browning, and sympathetic-immune interactions. Preclinical studies have highlighted the potential of EA to enhance satiety signals, restore gut microbiota balance, suppress inflammasome activity, and promote white adipose tissue browning. Future research needs to prioritize human studies, elucidate neural circuitry, and optimize treatment protocols to translate preclinical findings into clinical practice.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 1","pages":"17"},"PeriodicalIF":3.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel Essigke, M Zaher Kalo, Lingsi Kong, Matthias Wörn, Mohammad-Khaled Saad, Kingsley Omage, Bernhard N Bohnert, Andreas L Birkenfeld, John P Atkinson, Xiaobo Wu, Ferruh Artunc
{"title":"Activation of the alternative complement pathway and its relevance for sodium retention in experimental nephrotic syndrome.","authors":"Daniel Essigke, M Zaher Kalo, Lingsi Kong, Matthias Wörn, Mohammad-Khaled Saad, Kingsley Omage, Bernhard N Bohnert, Andreas L Birkenfeld, John P Atkinson, Xiaobo Wu, Ferruh Artunc","doi":"10.1007/s00424-025-03136-x","DOIUrl":"10.1007/s00424-025-03136-x","url":null,"abstract":"<p><p>The complement component C3, factor B (FB) and factor D (FD) belong to the alternative complement pathway and have been identified in urine samples from nephrotic mice. However, it is not yet known whether these factors are involved in mediating sodium retention in nephrotic syndrome (NS). Here we used a genetic mouse model of NS based on an inducible podocin deletion (Nphs2<sup>Δipod</sup>). These mice were intercrossed with mice deficient for FB, FD or C3, yielding Nphs2<sup>Δipod</sup>*Cfb<sup>-/-</sup>, Nphs2<sup>Δipod</sup>*Cfd<sup>-/-</sup> or Nphs2<sup>Δipod</sup>*C3<sup>-/-</sup> mice, respectively. NS was induced after oral doxycycline treatment for 14 days. C3, FB and FD were detected in the nephrotic urine of Nphs2<sup>Δipod</sup> mice as well as fragments of C3 and FB, indicating intrarenal activation of the alternative complement pathway. Lack of FB and FD had no impact on the activation of C3. Immunohistochemistry demonstrated positive C3 staining in protein casts and within the proximal tubule. Nephrotic mice of all genotypes experienced similar proteolytic activation of the epithelial sodium channel ENaC, developed sodium retention (urinary sodium concentration < 20 mM) and body weight gain. This was associated with a stimulation of proteolytic processing of epithelial sodium channel ENaC in all genotypes. In conclusion, components of the alternative complement pathway are detectable and activated in nephrotic syndrome. Mice with deletion of C3, FB or FD are not protected from proteolytic ENaC activation and sodium retention in NS.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 1","pages":"16"},"PeriodicalIF":3.2,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12764515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The electrophysiology of ventricular cell pairs.","authors":"Massimiliano Zaniboni","doi":"10.1007/s00424-025-03132-1","DOIUrl":"10.1007/s00424-025-03132-1","url":null,"abstract":"<p><p>Modern cardiac electrophysiology is largely focused on global electrical properties of tissue, frequently assessed by extracellular electrical recordings or optical mapping, whereas studies on the microscopic nature of action potential conduction are more rare, though fundamental to understand the whole-heart behavior. The electrophysiological dynamics of two ventricular myocytes electrically connected via gap junctions is the simplest conceivable model to study the laws governing the conduction of the electrical impulse within the heart ventricles. Since the enzymatic dispersion of cardiac cells has made it possible to isolate and investigate cardiac cell pairs directly, additional techniques have been introduced to investigate the problem, including coupling clamp, dynamic clamp, and numerical simulations. The physiology of a ventricular cell pair allows to define the basic laws governing the electrotonic interaction between cardiac cells in the absence of factors, like fiber orientation, heterogeneous spatial dispersion of electrophysiological properties, complex interaction with vessels and fibrotic tissue, that play a significant role in multicellular tissue studies. However, these laws remain at the base of our understanding of cardiac electrical functioning and should be bear in mind when dealing with the complexity of the whole organ level. This review will face both the technical issues encountered with the studies of ventricular cell pairs as well as the results found by the different authors concerning the physiological electrical coupling between cells, their physiological and pharmacological modulation, and the complex interactions between the conducted action potentials in the two cells.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 1","pages":"15"},"PeriodicalIF":3.2,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12740972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Suzana Luisa Alves Fernandes, Yan Costa Gonçalves, Francisco Tadeu Rantin, Ana Lúcia Kalinin, José Wilson Magalhães Bassani, Rosana Almada Bassani, Guilherme Borges Pereira, Diana Amaral Monteiro
{"title":"Modulation of cardiac contractility and redox balance via cannabinoid type II receptor activation in healthy rats.","authors":"Suzana Luisa Alves Fernandes, Yan Costa Gonçalves, Francisco Tadeu Rantin, Ana Lúcia Kalinin, José Wilson Magalhães Bassani, Rosana Almada Bassani, Guilherme Borges Pereira, Diana Amaral Monteiro","doi":"10.1007/s00424-025-03143-y","DOIUrl":"10.1007/s00424-025-03143-y","url":null,"abstract":"<p><p>The activation of cannabinoid receptor type II (CB2r) has been demonstrated to provide cardioprotective benefits against heart diseases. Nevertheless, the physiological effects of CB2r activation in healthy myocardial tissue remain poorly understood. Given the current gap in knowledge, particularly relevant in light of the growing therapeutic use of cannabinoids, this study aimed to investigate the effects of a single intraperitoneal injection of the selective synthetic CB2r agonist HU-308 on ventricular contractility, the expression of Ca<sup>2+</sup>-handling proteins, cyclic adenosine monophosphate (cAMP) levels, and redox biomarkers in male Wistar rats. Isolated left ventricular strips from HU-308-treated animals exhibited significant improvements in force of contraction (Fc), cardiac pumping capacity (CPC), and the rates of contraction (+ dF/dt) and relaxation (-dF/dt). Treatment with the CB2r agonist increased myocardial cAMP levels and upregulated the expression of sarcoplasmic reticulum (SR) Ca<sup>2+</sup>-ATPase (SERCA2a), phospholamban (PLB), and Na<sup>+</sup>/Ca<sup>2+</sup> exchanger (NCX1). Additionally, HU-308 administration increased the glutathione (GSH)/oxidized glutathione (GSSG) ratio and the activity of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). Enhancement of the antioxidant defense system contributed to the maintenance of redox balance, as evidenced by decreased levels of lipid peroxidation (LPO), protein carbonyl (PC), and DNA strand breaks (DNA-sb). This study provides the first evidence that CB2r activation exerts antioxidative effects while enhancing both inotropy and lusitropy in the healthy rat myocardium, highlighting CB2r as a potential therapeutic target for preserving cardiac function.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 1","pages":"14"},"PeriodicalIF":3.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}