Acta Physiologica最新文献

{"title":"Targeting histone deacetylase 6 (HDAC6) in Duchenne muscular dystrophy: New insights into therapeutic potential","authors":"Alexis Osseni, Laurent Schaeffer","doi":"10.1111/apha.14256","DOIUrl":"10.1111/apha.14256","url":null,"abstract":"<p>Rodney and colleagues provide compelling evidence for the therapeutic potential of selective histone deacetylase 6 (HDAC6) inhibition in <i>mdx</i> mice, a widely used model of Duchenne muscular dystrophy (DMD).<span><sup>1</sup></span> Their study reveals that HDAC6 inhibition promotes enhanced autophagy through increased tubulin acetylation, offering new hope for treatment strategies targeting this critical enzyme. This research sheds light on the potential of HDAC6 inhibitors to address some of the key pathological features of DMD.</p><p>Duchenne muscular dystrophy is a severe, progressive neuromuscular disorder caused by mutations in the dystrophin gene on the X chromosome.<span><sup>2</sup></span> Affecting approximately 1 in 3500 male births, DMD leads to the absence of dystrophin, a structural protein that connects muscle fibers to the extracellular matrix. Without dystrophin, muscle cells are vulnerable to damage and progressive degeneration. DMD typically presents in early childhood, with delayed motor milestones, muscle weakness, and difficulty standing. As the disease progresses, children develop a characteristic waddling gait, difficulty climbing stairs, and progressive muscle loss, ultimately leading to wheelchair dependence by age 12. Complications such as skeletal deformities, breathing difficulties, and cardiomyopathy arise, and most patients do not survive beyond their 30s due to respiratory and cardiac failure.</p><p>Despite two decades of research, no cure for DMD exists, and current treatments remain limited to glucocorticoid therapy. Although innovative genetic approaches, such as exon skipping, gene editing with CRISPR/Cas9, and viral vector-mediated dystrophin delivery, show promise, challenges like inconsistent efficacy, off-target effects, and incomplete dystrophin restoration in muscle tissues—especially in the heart—have slowed progress. As a result, a more comprehensive treatment strategy, combining genetic and pharmacological approaches, is likely necessary to address the multifaceted nature of DMD.</p><p>Over the past 20 years, HDAC inhibitors have shown promise in pre-clinical DMD models. Givinostat, a pan-HDAC inhibitor, was recently FDA-approved for its ability to slow disease progression in ambulatory boys with DMD.<span><sup>3</sup></span> However, pan-HDAC inhibitors can have undesirable side effects, including genotoxicity and impaired DNA repair. To mitigate these risks, more selective HDAC inhibitors have been developed, with HDAC6 emerging as a particularly attractive target. HDAC6-specific inhibitors have been shown to have several advantages over pan-HDAC inhibitors, including a lack of severe side effects. For instance, <i>HDAC6 knockout</i> mice do not exhibit significant pathological features, suggesting that selective inhibition of HDAC6 may be safe and beneficial.<span><sup>4</sup></span></p><p>In animal models, HDAC6 inhibition has demonstrated therapeutic effects in a range of disorders, includi","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A potential link between enteric glia and the pathophysiology of diet-induced obesity and related metabolic diseases","authors":"Onesmo B. Balemba, Brian D. Gulbransen","doi":"10.1111/apha.14258","DOIUrl":"10.1111/apha.14258","url":null,"abstract":"<p>Enteric glia are a large population of peripheral neuroglia that accompany neurons in the enteric nervous system. These cells have diverse functions and engage in bidirectional communication with various cell types, including enteric neurons, immune cells, and possibly the gut microbiota.<span><sup>1, 2</sup></span> Enteric glia play important roles in maintaining gastrointestinal (GI) homeostasis, and it is thought that alterations in their functions could be pivotal in the development of GI disorders. For instance, gains or losses in glial functions contribute to abnormal gut barrier function, inflammation, immune activation, and motor control. Understanding mechanisms by which enteric glia serve as “guardians” of the mucosal barrier has been an area of considerable interest; however, their involvement in mucosal barrier dysfunction is still debated.<span><sup>3</sup></span></p><p>Inflammation caused by altered diet–gut microbiome–host interactions is considered an important driver of increased epithelial permeability in the development of obesity; yet the underlying mechanisms remain poorly understood.<span><sup>4, 5</sup></span> A recent study by D'Antongiovanni et al.<span><sup>6</sup></span> in Acta Physiologica Volume 240 addressed this issue by exploring potential contributions of enteric glia in gut barrier dysfunction driven by ingesting a Western (high-fat) diet. This study specifically focused on potential roles of inflammasome activation in glia as a potential contributor to diet-induced inflammation. The investigators approached this question using wild-type C57BL/6J and NLRP3-KO<sup>−/−</sup> mice fed a 60-kcal high-fat diet (HFD) or standard diet for 8 weeks and studied mucosal integrity by histology, immunolabeling, and western blot. Potential reactive gliosis processes and inflammasome activation were assessed by immunolabeling for glial fibrillary acidic protein (GFAP) and co-labeling for inflammasome components.</p><p>The data show that mice consuming a HFD for 8 weeks increased body weight, altered colon mucus composition by decreasing acidic mucins, disrupted epithelial barrier integrity, increased GFAP-positive glial cells (gliosis), and triggered NLRP3 inflammasome activation. Surprisingly, HFD-NLRP3<sup>−/−</sup> mice failed to gain weight on the HFD and did not exhibit signs of enteric gliosis or altered mucus composition and epithelial barrier integrity. Based on these results, the authors suggested that inflammasome activation is involved in causing obesity, impairing the mucosal barrier, and activating gliosis. To test this concept more directly, the investigators turned to in vitro coculture experiments with a rat-transformed cell line used to model enteric glia (CRL-2690) and a rat intestinal epithelial cell (IEC) line. Challenging cultures with a combination of lipopolysaccharide (LPS) and palmitate was then used to broadly test whether dietary saturated fatty acids and endotoxins disrupt the epithelial barrier ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Did you know: Kangaroos are resistant to ventricular arrhythmia","authors":"Kirstine Calloe, Stefan M Sattler, Julie Norup Hertel, Carsten Grøndahl, Stamatios Alan Tahas, Morten B. Thomsen","doi":"10.1111/apha.14257","DOIUrl":"10.1111/apha.14257","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chloride fluxes and GABA release sustain inhibition in the CNS: The role for Bestrophin 1 anion channels","authors":"Alexei Verkhratsky, Verena Untiet, Vladimir V. Matchkov","doi":"10.1111/apha.14254","DOIUrl":"10.1111/apha.14254","url":null,"abstract":"<p>In the current issue of <i>Acta Physiologica</i>, Di Papma et al.<span><sup>1</sup></span> revealed a widespread brain expression of Ca<sup>2+</sup>-dependent anion (chloride) channel Bestrophin 1 (Best1) in both neurones and neuroglia. Chloride ions (Cl<sup>−</sup>) are indispensable for ionotropic inhibition of neurons in the central nervous system (CNS). This inhibition is mainly mediated by GABA<sub>A</sub> and glycine pentameric receptors, the ligand-gated anion channels. Thus, controlling Cl<sup>−</sup> homeostasis is paramount for balancing inhibition and excitation in the nervous circuits, which is critical for CNS function. An aberrant inhibition in the nervous circuits leads to many neurological and neuropsychiatric diseases, including epilepsy and mood disorders.<span><sup>2, 3</sup></span></p><p>Homeostasis of Cl<sup>−</sup> in the CNS is functionally segregated between neurones and astrocytes. In the mature brain, neurones keep cytoplasmic Cl<sup>−</sup> concentration ([Cl<sup>−</sup>]<sub><i>i</i></sub>) low at around ~5–10 mM, while astrocytes maintain high [Cl<sup>−</sup>]<sub><i>i</i></sub> in the range of 30–60 mM.<span><sup>4</sup></span> This disparity defines the functional outcome of the opening of anion channels: in neurones an opening of anion channels mediates Cl<sup>−</sup> influx (which results in hyperpolarization which inhibits neuronal activity), whereas in astrocytes these channels mediate depolarising Cl<sup>−</sup> efflux. Such an opposite arrangement of the [Cl<sup>−</sup>]<sub><i>i</i></sub> homeostasis is critical for maintaining synaptic and extrasynaptic neuronal inhibition. That is, Cl<sup>−</sup> influx into neurones may deplete Cl<sup>−</sup> from the extracellular space but Cl<sup>-</sup> is replenished by a continuous supply of Cl<sup>−</sup> ions from astrocytes.<span><sup>5</sup></span> This coordinated Cl<sup>−</sup> movement between cells and extracellular space is greatly facilitated by a close synaptic association of neuronal and astrocytic compartments, which form a multipartite synapse and a synaptic cradle.<span><sup>6</sup></span> At the inhibitory synapses, the postsynaptic neuronal specialization, as well as astrocytic perisynaptic leaflets, possess GABA<sub>A</sub> receptors.<span><sup>5</sup></span> Hence, presynaptic GABA release opens anion channels in both neuronal and astrocytic membranes. Considering that extracellular Cl<sup>−</sup> concentration can be less than the presumed 120 mM,<span><sup>7</sup></span> astrocytic Cl<sup>−</sup> supply is critical for sustaining inhibitory synaptic transmission. Indeed, optogenetic manipulations with astrocytic [Cl<sup>−</sup>]<sub><i>i</i></sub> substantially affect neuronal inhibition.<span><sup>4</sup></span></p><p>Another key player in Cl<sup>−</sup> homeostasis in the brain tissue is represented by Ca<sup>2+</sup>-activated Cl<sup>−</sup> channels that link together cells excitation, expressed as an intracellular Ca<sup>2+</sup> raise, an","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Beneficial effects of MGL-3196 and BAM15 combination in a mouse model of fatty liver disease”","authors":"","doi":"10.1111/apha.14250","DOIUrl":"10.1111/apha.14250","url":null,"abstract":"<p>Zhou, M., Li, C., Byrne, F. L., Vancuylenburg, C. S., Olzomer, E. M., Hargreaves, A., Wu, L. E., Shackel, N. A., Santos, W. L., &amp; Hoehn, K. L. Beneficial effects of MGL-3196 and BAM15 combination in a mouse model of fatty liver disease. <i>Acta Physiologica</i>. 2014; 240(10): e14217. https://doi.org/10.1111/apha.14217</p><p>In Figure 1A, the compound structure of MGL-3196 is incorrect due to an extra bond between the Cl and N. The corrected structure (below) has the bond between the Cl and N removed.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14250","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation","authors":"Michael W. Schleh,&nbsp;Benjamin J. Ryan,&nbsp;Cheehoon Ahn,&nbsp;Alison C. Ludzki,&nbsp;Douglas W. Van Pelt,&nbsp;Lisa M. Pitchford,&nbsp;Olivia K. Chugh,&nbsp;Austin T. Luker,&nbsp;Kathryn E. Luker,&nbsp;Dmitri Samovski,&nbsp;Nada A. Abumrad,&nbsp;Charles F. Burant,&nbsp;Jeffrey F. Horowitz","doi":"10.1111/apha.14249","DOIUrl":"10.1111/apha.14249","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin-mediated glucose uptake.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Seventeen adults with obesity (BMI: 36 ± 3 kg/m²) completed a 2 h hyperinsulinemic–euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (<i>n</i> = 7) and LOW (<i>n</i> = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW&lt; 400; HIGH &gt;550 nmol/kgFFM/min/[μU/mL]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (<i>p</i> &lt; 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (<i>p</i> = 0.01). Additionally, insulin receptor-β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (<i>p</i> &lt; 0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IRβ and downstream insulin-signalling proteins in LOW.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential production of mitochondrial reactive oxygen species between mouse (Mus musculus) and crucian carp (Carassius carassius)","authors":"Lucie Gerber,&nbsp;May-Kristin Torp,&nbsp;Göran E. Nilsson,&nbsp;Sjannie Lefevre,&nbsp;Kåre-Olav Stensløkken","doi":"10.1111/apha.14244","DOIUrl":"10.1111/apha.14244","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In most vertebrates, oxygen deprivation and subsequent re-oxygenation are associated with mitochondrial impairment and excess production of reactive oxygen species (ROS) like hydrogen peroxide (H₂O₂). This in turn triggers a cascade of cell-damaging events in a temperature-dependent manner. The crucian carp (<i>Carassius carassius</i>) is one of few vertebrates that survives months without oxygen at cold temperatures and overcomes oxidative damage during re-oxygenation periods. Mitochondria of this anoxia-tolerant species therefore serve as an excellent model in translational research to study adaptation and resilience to low oxygen conditions and thermal variability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we used high-resolution respirometry on isolated mitochondria from hearts of crucian carp and the anoxia-intolerant mouse (<i>Mus musculus</i>), at 37 and 8°C; two temperatures relevant for transplantation medicine (i.e., graft preservation and subsequent rewarming).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We find: (1) a striking difference in H₂O₂ release between the two species at 37°C despite comparable mitochondrial efficiency and capacity, (2) a massive H₂O₂ release after inhibition of complex V in mouse at 37°C that is absent in crucian carp, and prevented in mouse by incubation at 8°C or uncoupling with a protonophore at 37°C, and (3) indications that differences in mitochondrial complex I and II capacity and thermal sensitivity influence the release of mitochondrial H₂O₂ relative to respiration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings provide comparative insights into a spectrum of mitochondrial adaptations in vertebrates and the importance of thermal variability. Furthermore, the species- and temperature-related changes associated with mitochondria highlighted in this study may help identify mitochondria-based targets for translational medicine.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A quantitative analysis of bestrophin 1 cellular localization in mouse cerebral cortex","authors":"Michael Di Palma,&nbsp;Wuhyun Koh,&nbsp;C. Justin Lee,&nbsp;Fiorenzo Conti","doi":"10.1111/apha.14245","DOIUrl":"10.1111/apha.14245","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Calcium-activated ligand-gated chloride channels, beyond their role in maintaining anion homeostasis, modulate neuronal excitability by facilitating nonvesicular neurotransmitter release. BEST1, a key member of this family, is permeable to γ-aminobutyric acid (GABA) and glutamate. While astrocytic BEST1 is well-studied and known to regulate neurotransmitter levels, its distribution and role in other brain cell types remain unclear. This study aimed to reassess the localization of BEST1 in the mouse cerebral cortex.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined the localization and distribution of BEST1 in the mouse parietal cortex using light microscopy, confocal double-labeling with markers for astrocytes, neurons, microglia, and oligodendrocyte precursor cells, and 3D reconstruction techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the cerebral cortex, BEST1 is more broadly distributed than previously thought. Neurons are the second most abundant BEST1⁺ cell type in the cerebral cortex, following astrocytes. BEST1 is diffusely expressed in neuronal somatic and neuropilar domains and is present at glutamatergic and GABAergic terminals, with a prevalence at GABAergic terminals. We also confirmed that BEST1 is expressed in cortical microglia and identified it in oligodendrocyte precursor cells, albeit to a lesser extent.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Together, these findings suggest that BEST1's role in controlling neurotransmission may extend beyond astrocytes to include other brain cells. Understanding BEST1's function in these cells could offer new insights into the molecular mechanisms shaping cortical circuitry. Further research is needed to clarify the diverse roles of BEST1 in both normal and pathophysiological conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcineurin inhibitors and the renin–angiotensin–aldosterone system","authors":"Mesut Berber,&nbsp;David Penton","doi":"10.1111/apha.14248","DOIUrl":"10.1111/apha.14248","url":null,"abstract":"<p>Calcineurin inhibitors (CnIs) are effective immunosuppressants with decades of accumulated experience in treating immune disorders and, most notably, solid organ transplantation. While CnIs have significantly increased graft survival and transformed the patient standard of care, their use has been overshadowed by a number of undesired side effects. For instance, CnI-associated nephrotoxicity has been reported since early studies and remains a major therapeutic concern. The occurrence of several ion imbalances alongside hypertension was also noted early on, indicating the involvement of the renin–angiotensin–aldosterone system (RAAS) in CnI-mediated toxicity. However, the literature in this field is crowded with conflicting reports from clinical trials as well as studies using animal and invitro models. With this review, we aim to provide a structured and updated overview of the physiological and pathophysiological evidence supporting the involvement of the classical RAAS in CnI-associated toxicity.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High chloride induces aldosterone resistance in the distal nephron","authors":"Helga Vitzthum,&nbsp;Nina Hauswald,&nbsp;Helena Pham,&nbsp;Leya Eckermann-Reimer,&nbsp;Catherine Meyer-Schwesinger,&nbsp;Heimo Ehmke","doi":"10.1111/apha.14246","DOIUrl":"10.1111/apha.14246","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Increasing the dietary intake of K⁺ in the setting of a high salt intake promotes renal Na⁺ excretion even though K⁺ concurrently enhances the secretion of aldosterone, the most effective stimulus for renal Na⁺ reabsorption. Here, we questioned whether in the high salt state a mechanism exists, which attenuates the aldosterone response to prevent renal Na⁺ reabsorption after high K⁺ intake.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice were fed diets containing varying amounts of Na⁺ combined with KCl or KCitrate. Murine cortical connecting duct (mCCDcl1) cells were cultured in media containing normal or high [Cl⁻]. The response to aldosterone was analyzed by high-resolution imaging and by biochemical approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The canonical cellular response to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR) and activation of the epithelial Na⁺ channel ENaC was repressed in Na⁺-replete mice fed a high KCl diet, even though plasma aldosterone concentrations were increased. The response to aldosterone was restored in Na⁺-replete mice when the extracellular [Cl⁻] increase was prevented by feeding a high KCitrate diet. In mCCDcl1 cells, an elevated extracellular [Cl⁻] was sufficient to disrupt the aldosterone-induced MR translocation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings indicate a pivotal role for extracellular [Cl⁻] in modulating renal aldosterone signaling to adapt MR activation by a high K⁺ intake to the NaCl balance. An impairment of [Cl⁻]-mediated aldosterone resistance may contribute to excessive MR activation by aldosterone in the presence of a high salt intake characteristic of the Western diet, resulting in an inappropriate salt reabsorption and its downstream detrimental effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}