Pflugers Archiv : European journal of physiology最新文献

{"title":"Ethanol-induced dysfunction of the mesenteric perivascular adipose tissue is driven by mineralocorticoid receptors.","authors":"Ivis V O Martins, Thales M H Dourado, Gustavo F Pimenta, Marcela M Blascke de Mello, Aline G Fedoce, Wanessa M C Awata, Michele M Castro, Rita C Tostes, Carlos R Tirapelli","doi":"10.1007/s00424-025-03094-4","DOIUrl":"10.1007/s00424-025-03094-4","url":null,"abstract":"<p><p>The renin-angiotensin-aldosterone system (RAAS) is critical in ethanol-induced vascular dysfunction. Mineralocorticoid receptors (MR) trigger ethanol-induced vascular hypercontractility through pro-oxidative and pro-inflammatory effects. However, the contribution of MR to ethanol-induced perivascular adipose tissue (PVAT) dysfunction is unknown. Appreciating the importance of MR to PVAT dysfunction in distinctive pathological conditions, we investigated whether MR would play a role in ethanol-induced PVAT dysfunction. With this purpose, male Wistar Hannover rats were treated with ethanol 20% (in volume ratio) and/or potassium canrenoate [a MR antagonist (MRA); 30 mg/kg/day, gavage] for 5 weeks. Ethanol increased the circulating levels of aldosterone and impaired acetylcholine-induced relaxation of mesenteric arteries with, but not without PVAT. Antagonism of MR prevented ethanol-induced impairment in acetylcholine relaxation as well as the reduction of leptin levels and reactive oxygen species (ROS) overproduction in the mesenteric PVAT (mPVAT) from ethanol-treated rats. Ethanol promoted neutrophil accumulation and augmented the concentration of tumor necrosis factor (TNF)-α in the mPVAT and these responses were prevented by the MRA. Functional assays showed that tiron [a scavenger of superoxide (O₂^•-)] and etanercept (an antibody anti-TNF-α) failed to reverse the impairment of acetylcholine-induced relaxation promoted by ethanol. In mesenteric arteries, antagonism of MR prevented ROS generation, lipoperoxidation, and increased TNF-α levels induced by ethanol. In conclusion, our findings suggest that MR is involved in ethanol-induced dysfunction of mPVAT. This study enhances our understanding of how ethanol exerts harmful effects on the cardiovascular system, highlighting PVAT as a target for these detrimental effects.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"919-933"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079399","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":"Role of oxidative/nitrosative stress in dysfunction of rat's intracerebral parenchymal arterioles in low sodium environment in the presence of vasopressin.","authors":"Marta Aleksandrowicz","doi":"10.1007/s00424-025-03097-1","DOIUrl":"10.1007/s00424-025-03097-1","url":null,"abstract":"<p><p>Hyponatremia is the most common electrolyte disturbance in hospitalized patients. Symptoms of hyponatremia include attention deficits and cognitive impairments. The cause of such abnormalities may be disturbances in the regulation of microcirculation. Previous studies have shown that increased vasopressin (AVP) concentration to 15 pg/ml in the presence of decreased Na⁺ concentration to 121 mM, which mimics AVP-associated hyponatremia in vivo leads to dysfunction, i.e., constriction and impaired endothelial regulation of small intracerebral blood vessels-parenchymal arterioles (PA). One of the possible causes of this dysfunction may be excessive production of superoxide anion (O2^•-). The superoxide anion binds nitric oxide (NO) in a reaction that produces aggressive nitrogen-free radical, peroxynitrite (ONOO^-), which simultaneously reduces the bioavailability of NO. The present studies were performed in the organ chamber on isolated, perfused, and pressurized rats' PA in low sodium environment in the presence of AVP. These studies aimed to investigate the mechanism leading to PA dysfunction, i.e., constriction and disturbed endothelial regulation. L-NAME (N(ω)-nitro-L-arginine methyl ester) did not elicit constriction of PA, indicating reduced involvement of NO in maintaining basal tone of PA. Vasopressin V_1a receptor antagonist (SR 49059), endothelin ET_A/ET_B receptors antagonist (PD 142,893), peroxynitrite decomposition catalyst (FeTMPyP) and ROS scavengers: superoxide dismutase (SOD) and catalase (CAT) improved studied responses. Dihydroethidium (DHE) staining confirmed the increased superoxide anion formation in low sodium environment in the presence of AVP. Thromboxane A₂/prostaglandin H₂ receptor blocker (SQ 29,548), an inhibitor of the production of 20-HETE (HET0016), and L-arginine, a precursor of NO, did not improve dysfunctions of PA. Thus, in studied conditions, endothelial dysfunction occurs due to oxidative/nitrosative stress. These findings provide novel insight into the detrimental effects of decreased Na⁺ concentration in the presence of increased AVP concentration that mimic hyponatremia, on the regulation of cerebral microcirculation.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"993-1005"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161246","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":"Targeting NLRP3 inflammasome attenuates cardiac pyroptosis and fibrosis in estrogen-deficient diabetic rats.","authors":"Sukanya Phungphong, Phichaya Suthivanich, Worakan Boonhoh, Chuchard Punsawad, Zhaokang Cheng, Tepmanas Bupha-Intr","doi":"10.1007/s00424-025-03092-6","DOIUrl":"10.1007/s00424-025-03092-6","url":null,"abstract":"<p><p>Cardiac diastolic dysfunction is a hallmark of diabetic cardiomyopathy (DCM), particularly in postmenopausal women where estrogen deficiency exacerbates cardiac remodeling. This study investigated the roles of NLRP3 inflammasome activation and cardiac mast cell (CMC) behavior in diabetic ovariectomized (OVX) rat models. Female Wistar rats were divided into five groups: sham-operated, OVX, diabetic (Sham-DM), OVX-diabetic (OVX-DM), and OVX-DM treated with the NLRP3 inhibitor MCC950. Diabetes was induced using a high-calorie quick fat diet (13.8% crude fat, 24.35% crude protein, 25% sucrose; 406.80 kcal/100 g) followed by a single intraperitoneal injection of streptozotocin (30 mg/kg). MCC950 (10 mg/kg BW, intraperitoneally) was administered daily for 4 weeks. Echocardiography revealed significant diastolic dysfunction in OVX-DM rats, with increased left ventricular internal diameter (LVIDd) and reduced mitral valve E/A ratio, while MCC950 treatment partially restored diastolic function (p < 0.05). Masson's trichrome staining showed increased myocardial fibrosis in OVX-DM rats (2.59 ± 0.20%) compared to Sham-DM (1.94 ± 0.16%, p < 0.05), which was reduced with MCC950 treatment (0.88 ± 0.13%, p < 0.05). Western blot analysis demonstrated elevated expression of NLRP3, cleaved caspase-1, IL-1β, and GSDMD-N in OVX-DM hearts. MCC950 significantly reduced cleaved caspase-1, IL-1β, and GSDMD-N expression without altering NLRP3 protein levels. Additionally, mast cell degranulation was markedly increased in OVX-DM rats (62.14%) compared to controls (P < 0.05) and was attenuated by MCC950 (31.06%, P < 0.05). These findings suggest that NLRP3 inflammasome activation under conditions of estrogen deficiency and diabetes contributes to myocardial pyroptosis and mast cell degranulation, driving cardiac remodeling in postmenopausal DCM. Targeting NLRP3 pathways may provide an effective therapeutic strategy to mitigate diastolic dysfunction, fibrosis, and inflammation in diabetic hearts.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"935-952"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094556","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":"The relevance of RNA-DNA interactions as regulators of physiological functions.","authors":"Julia Stötzel, Timothy Warwick, Praveenya Tirunagari, Ralf P Brandes, Matthias S Leisegang","doi":"10.1007/s00424-025-03091-7","DOIUrl":"10.1007/s00424-025-03091-7","url":null,"abstract":"<p><p>RNA-DNA interactions are fundamental to cellular physiology, playing critical roles in genome integrity, gene expression, and stress responses. This review highlights the diverse structures of RNA-DNA hybrids, including R-loops, RNA-DNA triplexes, and RNA-DNA hybrid G-quadruplexes (hG4s) and their relevance in physiology. R-loops are formed during transcription and replication, which regulate gene expression and chromatin dynamics but can also threaten genome stability. RNA-DNA triplexes, often formed by long noncoding RNAs (lncRNAs) such as FENDRR and MEG3, recruit chromatin modifiers like Polycomb repressive complex 2 to modulate gene expression, influencing organogenesis and cell specification. hG4s, formed by guanine-rich sequences in RNA and DNA, regulate transcription termination and telomere stability. Through this, hG4s can affect gene suppression and replication regulation. RNA-DNA hybrids are tightly regulated by helicases, RNase H enzymes, and topoisomerases, with altered regulation linked to genomic instability and disease. This review discusses the complexity of RNA-DNA interactions and their recently identified contributions to cellular physiology.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"889-901"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111601","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":"SECS, drugs, and Rac1&Rho: regulation of EnNaC in vascular endothelial cells.","authors":"Benedikt Fels, Felix Fischer, Lisbeth Herrnboeck, David Beckers, Leon Niedzielski, Paul Roche, Alexandra Straeter, Ioana Alesutan, Johanna-Theres Borutta, Frederic Jaisser, Olivier Staub, Jakob Voelkl, Kristina Kusche-Vihrog","doi":"10.1007/s00424-025-03093-5","DOIUrl":"10.1007/s00424-025-03093-5","url":null,"abstract":"<p><p>The endothelial ENaC (EnNaC) is mainly responsible for maintaining the mechanical properties of the endothelial cell surface, the sensitivity to the shear forces of the streaming blood and thus for vascular function. The correlation between EnNaC surface expression, the dynamics of the actin cortex, the mechanical stiffness, and nitric oxide release indicates a close structure-function relationship. Mechanical flexibility of the endothelial surface has been associated with proper vascular function, while chronic stiffening leads to endothelial dysfunction and the so-called 'stiff endothelial cell syndrome' (SECS). With the help of atomic force microscopy (AFM)-based nanoindentation and immunofluorescence staining in vitro and ex vivo, we investigated the underlying cellular mechanisms and signalling pathways of EnNaC-dependent endothelial behaviour. We were able to show that the interaction between EnNaC and the cortical cytoskeleton is mediated by the small GTPases RhoA, Rac1, and the Arp2/3 complex. The functional inhibition of EnNaC by the drugs amiloride and benzamil led to membrane removal of the channel within minutes. Furthermore, we could observe an involvement of mineralocorticoid receptor, SGK1 and Nedd4-2 in regulation of endothelial cell stiffness. Our study contributes further insights on complex regulation of EnNaC and elucidates its interaction with the actin cytoskeleton, which could be central to its role as a key regulator of vascular function in health and disease.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"977-992"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120514","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":"Thermosensitivity of TREK K2P channels is controlled by a PKA switch and depends on the microtubular network.","authors":"Sönke Cordeiro, Marianne Musinszki","doi":"10.1007/s00424-025-03089-1","DOIUrl":"10.1007/s00424-025-03089-1","url":null,"abstract":"<p><p>Temperature sensing is an essential component of animal perception and enables individuals to avoid painful or lethal temperatures. Many temperature sensors in central and peripheral neurons are ion channels. Here, we focus on the thermosensitive TREK/TRAAK subfamily of K2P channels-the only known K⁺ selective thermosensitive channels. The C-terminal domain is essential for the temperature activation of TREK channels, but the mechanism of temperature sensation and the nature of the temperature sensor are unknown. We studied the thermosensitivity of representatives of all K2P channel subfamilies and identified TREK-1 and TREK-2 as the only thermosensitive K2P channels, while TRAAK, the third member of the mechano-gated subfamily, showed no temperature dependence. We transferred the thermosensitivity of TREK-1 to TRAAK channels by exchanging the C-termini, demonstrating that the C-terminal domain is sufficient to confer thermosensitivity. By gradually truncating the C-terminus, we isolated a specific temperature responsive element (TRE) consisting of 18 amino acids that constitutes a unique feature in mammalian thermosensitive channels. Within this TRE lie both the binding domain for microtubule associated protein 2 (MAP2) and the PKA phosphorylation site. Pharmacological disruption of the microtubular network as well as the loss of the MAP2 binding site suppressed the temperature response, and PKA activation completely abolished temperature sensitivity. Thus, the connection to the microtubular network enables the thermosensitivity of TREK channels, which is not intrinsic to the channel itself, while the PKA-mediated phosphorylation status acts as a switch that determines if TREK channels are thermosensitive at all.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"953-966"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079403","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 crucial decade that ion channels were proven to exist : The vision of Bertil Hille and Clay Armstrong and how it came through.","authors":"Luigi Catacuzzeno, Antonio Michelucci, Fabio Franciolini","doi":"10.1007/s00424-025-03085-5","DOIUrl":"10.1007/s00424-025-03085-5","url":null,"abstract":"<p><p>This retrospective begins with the first recording of the Na⁺ and K⁺ currents underlying the action potential in the squid giant axon reported by Hodgkin and Huxley in 1952, which made the question of where ions pass through the membrane more compelling. The notion of channels in the membrane had been around for quite some time but was so vague and contested that even the recording of Na⁺ and K⁺ currents through the membrane was not considered sufficient proof of their existence. In fact, Hodgkin and Huxley never referred to ion channels in their papers, only currents and conductances. The word \"channel\" remained somewhat left out from the scientific debate for almost another two decades, even though its idea was slowly making its way into the minds of discerning scientists. It is precisely this period that the present retrospective focuses on to understand the evolution of the ion channel concept from a speculative functional entity to a physical transmembrane object that serves the efficient and selective passage of ions. In this regard, the fundamental contribution of Bertil Hille and Clay Armstrong in promoting this idea, in the cold attitude, when not open aversion, of much of the scientific community, is fully acknowledged. Mention should also be made of Erwin Neher and Bert Sakmann's patch-clamp technique, which made it possible to directly measure ion currents through individual channels, thus conclusively demonstrating their presence in cell membranes. The retrospective goes on to briefly show how the cloning of ion channels in the 1980s and the first X-ray crystallographic structures at the turn of the century fully confirmed the initial suggestions, and closes by illustrating the relevance of ion channels in biology and medicine.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"903-917"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027519","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":"Creatine monohydrate supplementation and NOX impact skeletal muscle microvascular blood flow: a pilot study.","authors":"Paul A Baker, Holly E Clarke, Cesar A Meza, Mostafa M Ali, Robert C Hickner","doi":"10.1007/s00424-025-03090-8","DOIUrl":"10.1007/s00424-025-03090-8","url":null,"abstract":"<p><p>Impaired blood flow and elevated reactive oxygen species (ROS) concentrations, generated primarily from NADPH oxidase (NOX), indicate risk for cardiovascular disease (CVD). Creatine monohydrate (CM) may reduce CVD risk by lowering ROS concentrations and increasing skeletal muscle microvascular blood flow (SMBF). To determine if NOX-derived ROS impairs SMBF and whether five days of CM supplementation reduces in-vivo ROS concentrations and improves SMBF. Seven individuals had two microdialysis probes placed (control (CON) and apocynin (APO): NOX inhibitor) in skeletal muscle to measure in-vivo ROS (Hydrogen Peroxide (H₂O₂)) concentrations and SMBF (ethanol outflow/inflow ratio, inversely related to blood flow) at rest and four hours post-meal consumption. Procedures were performed before (PRE) and after (POST) five days of CM supplementation (20 g/day). Dialysate H₂O₂ concentrations were lower in the APO probe compared to CON from 120-140 min (APO: 1.19 ± 0.39 µM; CON: 2.04 ± 0.95 µM, p = 0.039), 140-160 min (APO: 1.17 ± 0.37 µM; CON: 2.06 ± 0.98 µM, p = 0.034) and 160-180 min post meal ingestion (p ≤ 0.05). APO perfusion increased SMBF at 20-40 min, 120-140 min (APO: 0.61 ± 0.13; CON: 0.75 ± 0.09 µM, p = 0.048), 140-160 min (APO: 0.61 ± 0.12 µM; CON: 0.76 ± 0.14 µM, p = 0.046), 160-180 min, and 180-200 min post meal (p ≤ 0.05). Ethanol outflow/inflow ratio was lower (higher SMBF) POST CM supplementation compared to PRE CM supplementation at 0-20 min (p = 0.036) and 20-40 min (p = 0.049) following HC/HF meal consumption. Inhibition of NOX-derived ROS increased SMBF, suggesting that NOX activity may impair blood flow regulation over the duration of baseline and post-prandial time points. Further, CM supplementation could be an effective strategy for enhancing postprandial blood flow.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"967-976"},"PeriodicalIF":2.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187598","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 machinery of healthy vasodilatation: an overview.","authors":"Jana Pourová, Patrícia Dias, Milan Pour, Přemysl Mladěnka","doi":"10.1007/s00424-025-03096-2","DOIUrl":"https://doi.org/10.1007/s00424-025-03096-2","url":null,"abstract":"<p><p>Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. Its rapid and efficient regulation is secured by many interconnected physiological mechanisms, both at the level of the vascular smooth muscle and the endothelium. The purpose of this review is to provide an update of the current knowledge on the mechanisms of physiological vasodilatation. First, two principal intracellular signaling pathways linked to the activation of protein kinases PKA and PKG are introduced. Subsequently, the role of endothelium-derived relaxing factors together with the endothelium-dependent hyperpolarization is discussed. The roles of ion channels and gap junctions in the communication between endothelium and vascular smooth muscle cells are particularly discussed. Finally, principal vasodilatory stimuli (mechanical, thermal, chemical) and their mechanisms of action are briefly introduced.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234778","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":"Soft tissue calcifications in chronic kidney disease-beyond the vasculature.","authors":"Abul Fajol, Christian Faul","doi":"10.1007/s00424-025-03098-0","DOIUrl":"https://doi.org/10.1007/s00424-025-03098-0","url":null,"abstract":"<p><p>Inappropriate mineralization of soft tissues, also called ectopic calcification, is a well-known pathology in chronic kidney disease (CKD) that is associated with increases in systemic phosphate levels. Vascular calcification is a major contributor to cardiovascular injury and high mortality rates in CKD patients. Therefore, most animal and human studies have focused on the vasculature when describing ectopic calcifications and on the pathologic actions of elevated phosphate on vascular smooth muscle cells in this process. The extent of calcifications within soft tissues beyond the vasculature is not well described, and the involvement of cell types other than vascular smooth muscle cells is not clear. Here we provide a summary of CKD-associated extravascular calcifications in various tissues, which includes the lung, the gastrointestinal system, the liver, the skin, and the brain. Since phosphate elevations and widespread ectopic calcifications do not only occur in the context of CKD, but also in rare genetic disorders that affect the regulators of phosphate metabolism, the cellular transporters of phosphate and the factors protecting from mineral depositions outside of bone, we also discuss these pathologic scenarios. We describe different types of ectopic calcification to flesh out common aspects as well as differences in the potential mechanisms and target cell types. We postulate that phosphate elevations might act in various ways and on various tissues, which together causes a wide spectrum of phosphate-induced pathologies in CKD.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226190","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}