Acta Physiologica最新文献

{"title":"ITCHing To Halt Muscle Atrophy","authors":"César Vásquez-Trincado, Erin L. Seifert","doi":"10.1111/apha.70330","DOIUrl":"10.1111/apha.70330","url":null,"abstract":"<p>Skeletal muscle (SkM) mass is maintained by a coordinated balance between protein synthesis and degradation. Protein breakdown is primarily mediated by the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway [<span>1</span>]. This balance can change during normal muscle growth or in response to resistance exercise, increasing muscle mass through hypertrophy. In contrast, nutrient deprivation, aging, muscle disuse, cancer cachexia and sustained glucocorticoid exposure (e.g., pharmacological administration of dexamethasone) can shift this balance toward net protein loss, leading to muscle atrophy, or inability to increase mass. Although increased protein breakdown may be adaptive (e.g., during fasting), sustained protein catabolism can cause muscle weakness and reduce SkM metabolic capacity. Consistent with this metabolic decline, atrophic remodeling can also compromise mitochondrial homeostasis. Short-term muscle unloading promotes atrophy alongside a reduction in markers of mitochondrial biogenesis and a molecular pattern consistent with increased mitochondrial clearance through receptor-mediated mitophagy [<span>2</span>]. This imbalance may lower mitochondrial content and oxidative capacity in SkM.</p><p>Thrombospondin 1 (THBS1)—an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions—has emerged as a regulator of SkM remodeling [<span>3-5</span>]. In the context of muscle wasting, THBS1 expression is increased under several atrophic conditions, including denervation, fasting and aging [<span>4</span>]. Importantly, SkM-specific THBS1 overexpression induced myofiber atrophy, whereas deletion of <i>Thbs1</i> attenuated muscle loss induced by denervation or fasting [<span>4</span>]. Mechanistically, THBS1 promoted atrophy through TGFβ-Smad2/3-ATF4 signaling and positive modulation of the UPS and autophagy-lysosome pathway [<span>4</span>]. These findings identify THBS1 as a major positive regulator of SkM atrophy, highlighting the importance of understanding how its expression is controlled.</p><p>The recent article by Yu et al. in Acta Physiologica identified ITCH (AIP4) as a regulator of THBS1 protein degradation [<span>6</span>]. ITCH belongs to the NEDD4 family of HECT-type E3 ubiquitin ligases, previously linked to the regulation of mitochondrial morphology, cholesterol content and mitochondria-dependent apoptotic signaling [<span>7</span>]. ITCH deficiency was also associated with impaired mitochondrial respiration and ATP production [<span>8</span>]. Yu et al. found that dexamethasone lowered ITCH expression and increased THBS1 levels in mice and C2C12 cells. ITCH overexpression (ITCH-OE) in murine SkM attenuated dexamethasone-induced muscle loss and the expression of atrophy-related genes (atrogin-1, myostatin and MuRF-1), while improving markers of mitochondrial biogenesis, such as NRF1, TFAM and PGC-1α. THBS1-OE could override the protective effects of ITCH-OE on dexamethasone-induced atrop","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163310","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":"Sex Hormone-Binding Globulin Limits Glucocorticoid-Induced Muscle Wasting by Preserving Estrogen-Dependent Repression of Catabolic Signaling","authors":"Junyong Park,&nbsp;Ah-Young Song,&nbsp;Hae-Rahn Bae,&nbsp;Eui-Ju Hong,&nbsp;Sang R. Lee","doi":"10.1111/apha.70332","DOIUrl":"10.1111/apha.70332","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Chronic glucocorticoid (GC) therapy induces severe metabolic complications, notably secondary sarcopenia driven by excessive glucocorticoid receptor (GR)-mediated catabolism. Although sex steroids protect skeletal muscle metabolism, the role of sex hormone-binding globulin (SHBG), the primary determinant of sex steroid bioavailability, in modulating local endocrine crosstalk under GC stress remains unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated the clinical correlation between serum SHBG and endocrine factors in a rheumatology cohort frequently exposed to GC. To establish causality and underlying mechanisms, male and female human SHBG-transgenic (<i>hSHBG</i>-Tg) mice, with or without gonadectomy, and C2C12 myoblasts were challenged with dexamethasone (DXM) to simulate GC-induced muscle atrophy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In patients with high cumulative GC exposure (≥ 10,000 mg), circulating SHBG strongly inversely correlated with serum myostatin (<i>r</i> = −0.7153, <i>p</i> = 0.0076). In mice, <i>hSHBG</i>-Tg significantly rescued DXM-induced loss of muscle mass (quadriceps, gastrocnemius, tibialis anterior) and grip strength in females; notably, this protection was entirely abolished by ovariectomy. Mechanistically, <i>hSHBG</i>-Tg blunted GR Ser211 phosphorylation and downregulated the ubiquitin ligases <i>Fbxo32</i> and <i>Trim63</i>, while preserving estrogen receptor (ER) target genes (<i>Tff1</i> and <i>Pgr</i>). In vitro, estradiol antagonized DXM-induced <i>Trim63</i> transcription via ER, and co-treatment with SHBG sustained this anti-catabolic effect by extending estradiol bioavailability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>SHBG acts as a promoter of estrogen bioavailability that coordinates a protective endocrine crosstalk, counteracting GR-driven catabolism in female skeletal muscle. These findings identify SHBG as a key metabolic determinant and a promising therapeutic target to prevent corticosteroid-induced muscle wasting.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163341","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":"From Inflammation Resolution to Immune Cell Fate: Maresin 2 in Hypertensive Vascular Remodeling","authors":"Lu Zhang,&nbsp;Ming-Sheng Zhou","doi":"10.1111/apha.70328","DOIUrl":"10.1111/apha.70328","url":null,"abstract":"&lt;p&gt;Inflammation is not simply terminated by the disappearance of an injurious stimulus; rather, its resolution is an active biological process coordinated by specialized pro-resolving mediators (SPMs) [&lt;span&gt;1&lt;/span&gt;]. Increasing evidence has implicated SPMs in vascular inflammation, endothelial dysfunction, and hypertension [&lt;span&gt;2, 3&lt;/span&gt;], but their potential to directly restrain vascular remodeling remains incompletely understood. In a recent issue of &lt;i&gt;Acta Physiologica&lt;/i&gt;, Peng et al. identify Maresin 2 (MaR2) as a novel regulator of hypertensive vascular remodeling and provide evidence that the actions of MaR2 extend beyond conventional suppression of inflammation [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The principal contribution of this study is the identification of a link between MaR2-mediated resolution and macrophage fibrotic plasticity. Using AngII-induced hypertension, Peng and colleagues show that MaR2 not only prevents hypertension-associated medial thickening and fibrosis but also retains efficacy when administered after hypertension has been established. Importantly, the therapeutic experiments are strengthened by the inclusion of a blood-pressure–matched hydralazine group. Despite achieving comparable blood-pressure reduction, hydralazine did not reproduce the structural and phenotypic benefits of MaR2, showing that MaR2 does not simply protect the vasculature as a consequence of lowering blood pressure, but exerts additional effects within the vascular wall. This distinction is particularly important because vascular remodeling can become partially uncoupled from hemodynamic load, and therefore normalization of blood pressure does not necessarily normalize the underlying cellular and extracellular-matrix pathology. More broadly, this finding shifts the therapeutic concept from controlling the hemodynamic trigger to modifying the biological response of the vessel wall to that trigger, an important distinction for chronic vascular disease.&lt;/p&gt;&lt;p&gt;Mechanistically, the study moves the SPM field beyond the familiar concept of cytokine suppression toward regulation of immune-cell phenotype. RNA sequencing of bone marrow-derived macrophages identified enrichment of extracellular matrix and TGF-β-related pathways, while complementary in vivo and in vitro experiments demonstrated that MaR2 reduced macrophage accumulation and acquisition of collagen-, vimentin-, and α-SMA-associated pro-fibrotic characteristics. These observations are consistent with emerging evidence that macrophage plasticity contributes to fibrotic remodeling [&lt;span&gt;5&lt;/span&gt;]. Indeed, recent single-cell, lineage-tracing, and parabiosis studies have provided evidence that circulating monocyte-derived macrophages can acquire myofibroblast-like characteristics during AngII-induced hypertensive cardiac fibrosis [&lt;span&gt;6&lt;/span&gt;]. Thus, the conceptual advance of the present study is not simply the description of macrophage-to-myofibroblast-like phenotypes, but the demonstration that a","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70328","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101403","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":"Maresin 2 Attenuates Hypertensive Vascular Remodeling via Inhibiting Macrophage Infiltration and Pro-fibrotic Polarization","authors":"Shanshan Peng,&nbsp;Tao Wang,&nbsp;Jianfang Liu,&nbsp;Mengmeng Zhao,&nbsp;Zican Shen,&nbsp;Siqi Liu,&nbsp;Cheng Wei,&nbsp;Zihui Zheng,&nbsp;Yao Xu,&nbsp;Jun Wan,&nbsp;Menglong Wang","doi":"10.1111/apha.70318","DOIUrl":"10.1111/apha.70318","url":null,"abstract":"<div>\u0000 \u0000 <p>Immune-inflammatory responses are pivotal regulators of hypertensive vascular remodeling. Specialized pro-resolving mediators (SPMs), including Maresin 2 (MaR2), are endogenous anti-inflammatory molecules. However, the specific role of MaR2 in regulating hypertension and vascular remodeling, as well as its underlying mechanisms, remains unclear. In this study, a murine model of hypertension was induced by continuous infusion of Angiotensin II (AngII) at 1 μg/kg/min. MaR2 intervention (2 μg/kg/day) was administered either prophylactically (before model induction) or therapeutically (after model induction). Prophylactic MaR2 effectively prevented AngII-induced blood pressure elevation and vascular remodeling. Similarly, therapeutic administration after the establishment of hypertension with MaR2 significantly lowered blood pressure and attenuated medial thickening and fibrosis in the aorta and mesenteric arteries. Mechanistic studies revealed that MaR2 significantly inhibited macrophage infiltration and inflammatory responses within vascular tissues. Further in vitro and in vivo experiments confirmed that MaR2 effectively suppressed AngII-induced macrophage polarization toward a pro-fibrotic phenotype and reduced the acquisition of a myofibroblast-like phenotype (i.e., α-SMA expression) by macrophages by blocking the TGF-β/Smad3 signaling pathway. Notably, pharmacological activation of TGF-β/Smad signaling using SRI011381 partially counteracted the protective effects of MaR2 on vascular remodeling. MaR2 attenuates AngII-induced hypertension and vascular remodeling in association with reduced vascular macrophage accumulation and suppression of macrophage pro-fibrotic polarization, at least partly through regulation of TGF-β/Smad3 signaling. These findings identify MaR2 as a candidate pro-resolving intervention in an AngII-induced murine model of hypertension and support further mechanistic and translational evaluation in hypertension-associated vascular remodeling.</p>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101342","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":"Renal Myeloid Mechanisms, Cross-Talk in Hypertension","authors":"Luis Michea,&nbsp;Heddwen L. Brooks","doi":"10.1111/apha.70308","DOIUrl":"10.1111/apha.70308","url":null,"abstract":"<div>\u0000 \u0000 <p>Hypertension involves an impairment of renal sodium excretion along with activation of pro-inflammatory responses in the kidney. Dendritic cells (DCs) are professional antigen-presenting cells that sense disturbances in cell and tissue homeostasis to orchestrate T cell activation and recruitment. Renal DCs distribute as a cellular network throughout the renal interstitium, forming an interface between innate and adaptive immunity. Here, we explore what is known about renal cross-talk following prohypertensive stimuli, which modify renal DCs, T cell polarization, and renal function, leading to hypertension. We also present the phenotypic and functional heterogeneity of DCs, including literature on in vitro and in vivo signaling mechanisms in a variety of hypertensive models. Current studies indicate that renal sodium retention caused by prohypertensive stimuli requires DC function. The prohypertensive action of DCs also requires T cell function. Several cross-talk mechanisms have been proposed, such as signals from the kidney to the DC, including salt activation of DC's via RAAS receptor signaling, and DC-dependent recruitment of T cells to the kidney then promoting increased renal tubular sodium reabsorption. Knowledge gaps include specific functions of renal DC subtypes, sex differences in DC-mediated hypertension, and clinical studies on DC function in hypertension. The identification of mechanisms leading to renal DCs activation in hypertension may offer new strategies for the prevention and treatment of hypertension.</p>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126093","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":"Acute Kidney Injury and Chronic Kidney Disease","authors":"Henrik Dimke","doi":"10.1111/apha.70329","DOIUrl":"10.1111/apha.70329","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101322","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":"Baroreflex Loading Reveals Exaggerated Ventilatory Inhibition in Patients With Parkinson's Disease","authors":"Jhenny V. Neri,&nbsp;Jeann L. Sabino-Carvalho,&nbsp;Bruno M. Silva,&nbsp;Pedro R. P. Brandão,&nbsp;Fabrício da Silva,&nbsp;Paul J. Fadel,&nbsp;Lauro C. Vianna","doi":"10.1111/apha.70323","DOIUrl":"10.1111/apha.70323","url":null,"abstract":"&lt;p&gt;Did you know?&lt;/p&gt;&lt;p&gt;The influence of arterial baroreceptors extends beyond the short-term regulation of arterial blood pressure (BP) to the control of breathing, an interaction recognized since the early work of Heymans and Bouckaert demonstrating that sensory mechanisms arising from the carotid sinus and aortic regions contribute to reflex respiratory regulation [&lt;span&gt;1&lt;/span&gt;]. This work, recognized by the 1938 Nobel Prize in Physiology or Medicine, provided the foundation for subsequent studies showing that increases in BP can inhibit ventilation whereas decreases in pressure stimulate it, further supporting the concept that arterial baroreceptor input contributes to respiratory control.&lt;/p&gt;&lt;p&gt;The respiratory effects of arterial baroreceptor activation have subsequently been demonstrated across several species, including rodents, cats, dogs, piglets, and humans, although their magnitude and expression vary with species and experimental preparation. Early studies in humans suggested that the ventilatory inhibition accompanying pressor stimulation was mediated, at least in part, by arterial baroreceptor activation, with Heistad and colleagues showing that both phenylephrine and the nonadrenergic pressor agent angiotensin reduced minute ventilation and that the response to phenylephrine persisted during 100% oxygen, indicating that peripheral chemoreceptor mechanisms alone could not account for the response [&lt;span&gt;2&lt;/span&gt;]. This concept was later examined more systematically by Stewart and colleagues (2011) [&lt;span&gt;3&lt;/span&gt;] using the modified-Oxford technique to both unload and load the arterial baroreflex, while manipulating chemoreceptor activity with room air, hypoxia, and hypercapnic conditions. Despite marked changes in baseline ventilation during peripheral and central chemoreflex activation, ventilatory baroreflex sensitivity remained unchanged, although the operating point of the pressure–ventilation relationship shifted. These findings support a baroreceptor-mediated influence on ventilation that cannot be explained by changes in chemoreflex drive.&lt;/p&gt;&lt;p&gt;The neural organization underlying this response remains incompletely understood, but experimental evidence indicates that barosensory information can influence respiratory motor output through distributed medullary circuitry. In cats, arterial baroreceptor stimulation altered the activity of medullary raphe neurones while simultaneously prolonging expiration and reducing integrated phrenic activity, and functional interactions were identified between baroresponsive raphe neurones and inspiratory and expiratory neurones within the ventrolateral medulla [&lt;span&gt;4&lt;/span&gt;]. These observations led to the proposal that medullary raphe neuronal assemblies participate in transforming and transmitting barosensory information to the ventral respiratory group, suggesting a potential neural substrate through which changes in BP may influence respiratory timing and drive. The ventrolateral medul","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101412","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":"Klotho Deficiency Impairs Distal Potassium Homeostasis Through mTORC1-Dependent Suppression of ROMK","authors":"Wakako Kawarazaki,&nbsp;Nobuhiro Ayuzawa,&nbsp;Mitsuhiro Nishimoto,&nbsp;Daigoro Hirohama,&nbsp;Kohei Ueda,&nbsp;Takeshi Marumo,&nbsp;Toshiro Fujita","doi":"10.1111/apha.70325","DOIUrl":"10.1111/apha.70325","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Hyperkalemia is prevalent in the elderly, and underlying molecular mechanisms remain incompletely understood. We hypothesized that Klotho deficiency, a feature of aging, impairs renal potassium homeostasis and contributes to hyperkalemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Klotho heterozygous knockout (KLhet) mice, characterized by reduced Klotho levels, were used to investigate determinants of potassium handling, including renal outer medullary potassium channel (ROMK)1, the epithelial sodium channel (ENaC), which provides the driving force for ROMK-mediated potassium secretion, and plasma aldosterone concentration (PAC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>KLhet mice developed hyperkalemia with reduced urinary potassium excretion, accompanied by activation of renal mechanistic target of rapamycin complex 1 (mTORC1) signaling, indicated by increased phosphorylated S6, and decreased ROMK1 abundance in the plasma membrane fraction. Adrenal expression of aldosterone synthase <i>Cyp11b2</i> and PAC were elevated, and ENaC activity was enhanced, as evidenced by increased cleavage of α- and γ-ENaC subunits, partially compensating for impaired potassium excretion. Pharmacological ENaC inhibition with amiloride precipitated severe hyperkalemia in KLhet mice. In contrast, treatment with the mTORC1 inhibitor rapamycin or Klotho supplementation suppressed renal mTORC1 signaling, restored plasma membrane ROMK1 abundance, increased urinary potassium excretion, and normalized serum potassium levels, with reduced <i>Cyp11b2</i> expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Klotho deficiency impairs renal potassium handling through mTORC1-dependent downregulation of ROMK, with compensatory hyperaldosteronism and ENaC activation. These findings highlight an important role of the Klotho–mTORC1 axis in distal potassium homeostasis and its potential as a therapeutic target for Klotho deficiency–associated hyperkalemia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101378","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":"Fibroblast Growth Factor 2 Enhances Contraction of Arterioles in the Medulla Oblongata and the Basilar Artery in Mice With Chronic Kidney Disease","authors":"Liang Zhao,&nbsp;Xingyu Qiu,&nbsp;Chunxiang Xu,&nbsp;Gensheng Zhang,&nbsp;Nan Xu,&nbsp;Pontus B. Persson,&nbsp;Andreas Patzak,&nbsp;Jianhua Mao,&nbsp;En Yin Lai","doi":"10.1111/apha.70327","DOIUrl":"10.1111/apha.70327","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Chronic kidney disease (CKD) augments vascular contractility in multiple vascular beds. Fibroblast growth factor 2 (FGF2), whose expression is upregulated in CKD, acts pro-contractile by supporting vasoconstrictor capacity. Thus, the present study tests whether CKD enhances cerebrovascular contractile responses to vasoconstrictors and a role of FGF2 in this setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We established CKD in mice by 5/6 nephrectomy and a 6% NaCl diet. Cerebrovascular reactivity was assessed in isolated brain basilar arteries and brain medulla oblongata arterioles using wire myography and microperfusion, respectively. Contractile responses to angiotensin II (Ang II), norepinephrine (NE), and endothelin-1 (ET-1) were measured. Expression of FGF2 and FGF binding protein 1 (FGFBP1) was assessed by immunohistochemistry, enzyme-linked immunosorbent assays, qPCR, and western blot. The role of the FGF2 pathway was evaluated using the selective FGFR tyrosine kinase inhibitor BGJ398.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cerebrovascular contractile responses to Ang II, NE, and ET-1 were significantly enhanced in both the brain basilar artery and the brain medulla oblongata arterioles compared with the sham-operated group. FGF2 and FGFBP1 expression were upregulated in brain tissue after CKD, particularly in the medulla oblongata. Treatment with BGJ398 prevented the enhanced cerebrovascular contractile responses in CKD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>CKD enhances cerebrovascular contractile responses to vasoconstrictors, and this effect is mediated by activation of the FGF2 pathway. Targeting the FGF2 pathway may provide treatment of cerebrovascular dysfunction in CKD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101386","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":"Does the Heart Pace to the Drumbeat of Phosphate?","authors":"Jakob Voelkl,&nbsp;Ioana Alesutan","doi":"10.1111/apha.70326","DOIUrl":"10.1111/apha.70326","url":null,"abstract":"&lt;p&gt;In their recent work in Acta Physiologica [&lt;span&gt;1&lt;/span&gt;], Bertoli and colleagues pursued a puzzling question which was implied by previous observations: whether there is a link between mineral metabolism in the form of fibroblast growth factor 23 (FGF23) and sinus node function. In elaborate experiments, they investigated mouse sinoatrial cells and human pacemaker-like cardiomyocytes with patch-clamp experiments and observed that longer-term exposure of the cells to FGF23 increases action potential frequency via the funny &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;&lt;i&gt;f&lt;/i&gt;&lt;/sub&gt; current. Further experiments indicated that the effects are mediated via an FGF receptor (FGFR)/αKlotho complex (Figure 1). Although the elaborate methodology carries some inherent limitations and more translational validation is required, these findings now link mineral metabolism directly to cardiac control with potentially wide-ranging implications.&lt;/p&gt;&lt;p&gt;FGF23 is a potent phosphaturic hormone, physiologically produced mostly in bone during high phosphate conditions and in response to calcitriol, but also modified by parathyroid hormone, inflammation or iron deficiency [&lt;span&gt;2&lt;/span&gt;]. Expression of FGF23 was also reported in other tissues during pathological stress [&lt;span&gt;3&lt;/span&gt;]. The glycoprotein FGF23 binds to FGFRs, where a complex of FGFR1c and its co-receptor αKlotho is the most important to mediate its renal effects. FGF23 signaling inhibits tubular phosphate reabsorption, but also reduces calcitriol formation via CYP27B1 [&lt;span&gt;2&lt;/span&gt;]. αKlotho is expressed in the proximal and distal tubule of the kidney and can be shed as soluble αKlotho in blood and urine [&lt;span&gt;4&lt;/span&gt;]. In addition, functional αKlotho expression was also described in other sites such as the choroid plexus (with a considered role in mitigating brain inflammation) or the parathyroid glands (involved in parathyroid hormone regulation) [&lt;span&gt;5&lt;/span&gt;]. Both, Fgf23- or αKlotho-deficient mice develop severe hyperphosphatemia, causing a phenotype reminiscent of premature aging [&lt;span&gt;3, 5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;FGF23 has gained notoriety in chronic kidney disease (CKD), where reduced renal function leads to impaired phosphate excretion. In early CKD, phosphate excretion is maintained through rising FGF23 levels, but this compensation becomes insufficient as renal function deteriorates and serum phosphate rises. Notably, higher FGF23 has been linked to increased mortality in CKD, and cardiovascular effects have been discussed as potential contributors. In pre-clinical models, FGF23 augments cardiac hypertrophy in an αKlotho-independent manner through a FGFR4-calcineurin pathway, and can also modulate some inflammatory processes [&lt;span&gt;3&lt;/span&gt;]. In addition, FGF23 has been shown to cross the blood–brain barrier and to increase sympathetic tone via FGFR4 in the brain, promoting hypertension [&lt;span&gt;6&lt;/span&gt;]. In the context of cardiovascular effects, it seemed always an enigma that high expression of αKlotho was reported in t","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 11","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101371","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}