American journal of physiology. Regulatory, integrative and comparative physiology最新文献

{"title":"Strenuous training combined with erythropoietin induces red cell volume expansion-mediated hypervolemia and alters systemic and skeletal muscle iron homeostasis.","authors":"Benjamin J Ryan, David E Barney, Julie L McNiff, Devin J Drummer, Emily E Howard, Jess A Gwin, Christopher T Carrigan, Nancy E Murphy, Marques A Wilson, Stefan M Pasiakos, James P McClung, Lee M Margolis","doi":"10.1152/ajpregu.00164.2024","DOIUrl":"10.1152/ajpregu.00164.2024","url":null,"abstract":"<p><p>Strenuous physical training increases total blood volume (BV) through expansion of plasma volume (PV) and red cell volume (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, eight healthy nonanemic males were treated with EPO (50 IU/kg body mass, three times per week, sc) across 28 days of strenuous training (4 days/wk, exercise energy expenditures of 1,334 ± 24 kcal/day) while consuming a controlled, energy-balanced diet providing 39 ± 4 mg/day iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased (<i>P</i> < 0.01) RCV (13 ± 6%) and BV (5 ± 4%), whereas PV remained unchanged (<i>P</i> = 0.86). The expansion of RCV was accompanied by a large decrease in whole body iron stores, as indicated by decreased (<i>P</i> < 0.01) ferritin (-77 ± 10%) and hepcidin (-49 ± 23%) concentrations in plasma. Training + EPO decreased (<i>P</i> < 0.01) muscle protein abundance of ferritin (-25 ± 20%) and increased (<i>P</i> < 0.05) transferrin receptor (47 ± 56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen-carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole body and skeletal muscle iron stores.<b>NEW & NOTEWORTHY</b> Strenuous exercise training combined with erythropoietin (EPO) treatment increases blood volume, driven exclusively by red cell volume expansion. This hematological adaptation results in increased total oxygen-carrying capacity and hypervolemia. The marked upregulation of erythropoiesis with training + EPO reduces whole body iron stores and circulating hepcidin concentrations. The finding that the abundance of ferritin in muscle decreased after training + EPO suggests that muscle may release iron to support red blood cell production.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R473-R478"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypertension restricts leg blood flow and aggravates neuromuscular fatigue during human locomotion in males.","authors":"Taylor S Thurston, Joshua C Weavil, Hsuan-Yu Wan, Mark A Supiano, Philip A Kithas, Markus Amann","doi":"10.1152/ajpregu.00117.2024","DOIUrl":"10.1152/ajpregu.00117.2024","url":null,"abstract":"<p><p>Patients with hypertension (HTN) are characterized by exaggerated vascular resistance and mean arterial pressure (MAP) and a compromised leg blood flow (Q_L) response to exercise recruiting a small muscle mass. However, the impact of hypertension on peripheral hemodynamics and the development of neuromuscular fatigue during locomotor activities, which critically depends on Q_L, remain unknown. Eight HTN (143 ± 11 mmHg/95 ± 6 mmHg; 45 ± 13 yr) and eight matched (age and activity) controls (120 ± 6 mmHg/77 ± 7 mmHg; CTRL) performed constant-load cycling exercise at 25, 50, and 75 W (for 4 min each) and at 165 ± 41 W (for 5 min). Exercise-induced locomotor muscle fatigue was quantified as the pre- to postexercise change in quadriceps twitch-torque (Δ<i>Q</i>_tw, peripheral fatigue) and voluntary activation (ΔVA%, central fatigue). Q_L (Doppler ultrasound) and leg vascular conductance (LVC) were determined during cycling at 25, 50, and 75 W. Heart rate and ventilatory responses were recorded during all intensities. MAP during exercise was, on average, ∼21 mmHg higher (<i>P</i> = 0.002) and LVC ∼39% lower (<i>P</i> = 0.001) in HTN compared with CTRL. Q_L was consistently between 20 and 30% lower (<i>P</i> = 0.004), and heart rate was significantly higher in HTN. Exercise-induced peripheral (Δ<i>Q</i>_tw: -53 ± 19% vs. -25 ± 23%) and central (ΔVA%: -7 ± 5% vs. -3 ± 2%) fatigue was significantly greater in HTN compared with CTRL. In addition to an exaggerated MAP, LVC and Q_L were lower during exercise in HTN compared with CTRL. Given the critical role of Q_L in determining the development of neuromuscular fatigue, these hemodynamic impairments likely accounted for the faster development of neuromuscular fatigue characterizing hypertensive individuals during locomotor exercise. <b>NEW & NOTEWORTHY</b> The impact of primary hypertension on the cardiovascular and neuromuscular fatigue response to locomotor exercise is unknown. We compared central and peripheral hemodynamics and the development of central and peripheral fatigue during cycling exercise in patients with stage I/II hypertension and age- and activity-matched healthy individuals. In addition to a significantly elevated blood pressure, hypertensive patients were, compared with their nonhypertensive counterparts, also characterized by considerable leg blood flow limitations and impaired neuromuscular fatigue resistance.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R517-R524"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spontaneous and evoked angiotensin II sniffer cell activity in the lamina terminalis in vitro.","authors":"George E Farmer, J Thomas Cunningham","doi":"10.1152/ajpregu.00227.2023","DOIUrl":"10.1152/ajpregu.00227.2023","url":null,"abstract":"<p><p>Angiotensin II (ANG II) has been shown to have central nervous system effects. Although tissue renin-angiotensin systems (RAS) have been demonstrated in multiple tissues, the existence of a brain RAS is still a matter of debate. These studies test for angiotensin release from brain slices prepared from adult male Sprague-Dawley rats and male and female renin knock-out rats using Chinese hamster ovary cells modified to express both the angiotensin II type 1 receptor and a fluorescent calcium indicator. Sniffer cells were placed on the slices and calcium transients were measured from those located on or adjacent to the median preoptic nucleus with and without stimulation of the subfornical organ. Bath application of tetrodotoxin (1 µM) significantly attenuated spontaneous events while abolishing evoked sniffer cell activity. Bath application of dl-AP4 (10 µM, glutamatergic antagonist) did not affect either spontaneous or evoked release. Incubating the slices with fluorocitrate to inactive astrocytes did not influence sniffer cell activity in the MnPO. Pharmacological experiments indicate that ANG II release is largely both renin (aliskiren 10 µM) and ACE-1 (captopril 100 µM) dependent. However, experiments with brain slices prepared from male and female Renin knock-out rats suggest that alternative synthetic pathways may exist. Finally, these studies demonstrate that increases in ANG II release are observed following 7 days of chronic intermittent hypoxia. These studies suggest the existence of a tissue-specific RAS in the brain that involves canonical and alternative ANG II synthetic pathways and is upregulated in an animal model of sleep apnea.<b>NEW & NOTEWORTHY</b> These studies used Chinese hamster ovary cells that were cloned to express an angiotensin receptor (<i>At1ra</i>) and a calcium indicator (R-GECO) to detect the release of angiotensin from brain slices containing the lamina terminalis of rats. Some of the experiments use tissue from renin knockout rats. The results support the existence of an angiotensin system in the brain that may involve alternative synthetic pathways and is upregulated by intermittent hypoxia.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R486-R496"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Water deprivation induces a systemic pro-catabolic state that differentially affects oxidative and glycolytic skeletal muscles in male mice.","authors":"João da Cruz-Filho, Daniely Messias Costa, Tatiane Oliveira Santos, Raquel Prado da Silva, Hevely Catharine Anjos-Santos, Naima Jamile Santos Marciano, Roger Rodríguez-Gúzman, Ana Beatriz Henrique-Santos, João Eduardo Conceição Melo, Daniel Badauê-Passos, David Murphy, Andre Souza Mecawi, Danilo Lustrino","doi":"10.1152/ajpregu.00187.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00187.2024","url":null,"abstract":"<p><p>Dehydration, characterized by the loss of total body water and/or electrolytes due to diseases or inadequate fluid intake, is prevalent globally but often underestimated. Its contribution to long-term chronic diseases and sarcopenia is recognized, yet the mechanisms involved in systemic and muscle protein metabolism during dehydration remain unclear. This study investigated metabolic adaptations in a 36-hour water deprivation (WD) model of mice. Male C57BL/6 mice underwent 36-h WD or pair-feeding at rest, with assessments of motor skills along with biochemical, and metabolic parameters. Dehydration was confirmed by hypernatremia, body mass loss, hyporexia, and increased activity of vasopressinergic and oxytocinergic neurons compared to controls. These results were associated with liver mass loss, decreased glycaemia, and increased cholesterolemia. Additionally, increased VO₂ and a decreased respiratory exchange ratio indicated reduced carbohydrate consumption and potentially increased protein use during dehydration. Thus, skeletal muscle protein metabolism was evaluated due to its high protein content. In the oxidative muscles of the WD group, total and proteasomal proteolysis increased, which was associated with decreased Akt-mediated intracellular signaling. Interestingly, there was an increase in fiber cross-sectional area, likely due to higher muscle water content caused by increased intracellular osmolality induced by protein catabolism products. Conversely, no changes were observed in protein turnover or water content in glycolytic muscles. These findings suggest that short-term WD imposes a pro-catabolic state, depleting protein content in skeletal muscle. However, skeletal muscle may respond differently to dehydration based on its phenotype and might adapt for a limited time.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gulf toadfish (<i>Opsanus beta</i>) urinary bladder ion and water transport is enhanced by acclimation to higher salinity to serve water balance.","authors":"Erik John Folkerts, Martin Grosell","doi":"10.1152/ajpregu.00077.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00077.2024","url":null,"abstract":"<p><p>Marine teleosts experience ion gain and water loss in their natural habitats. Among other tissues, the urinary bladder epithelium of marine fishes has been shown to actively transport ions to facilitate water absorption. However, transport properties of the urinary bladder epithelium of marine fishes and its plasticity in altered ambient salinities is relatively under-investigated. We describe urinary bladder epithelium electrophysiology, water flux, and expressions of ion transporters in urinary bladder tissue of Gulf toadfish (<i>Opsanus beta</i>) acclimated to either 35 ppt or 60 ppt seawater. Water absorption in bladder sac preparations increased ~ 350% upon acclimation to 60 ppt. Increases in water transport coincided with a significant ~ 137% increase in urinary bladder tissue mucosal-to-serosal short circuit current (<i>I_sc</i>) and a ~ 56% decrease in tissue membrane resistance. Collectively, these metrics indicate that an active electrogenic system facilitates water absorption via Na⁺ (and Cl^-) transport in urinary bladder tissue. Furthermore, pharmacological inhibition of urinary bladder tissue <i>I_sc</i> and expression of a suite of ion transporters and channels previously unidentified in this tissue provide mechanistic insights into the transport processes responsible for water flux. Analysis of water transport to overall Gulf toadfish water balance reveals a modest water conservation role for the urinary bladder of ~ 0.5% of total water absorption in 35 ppt and 1.9% in 60 ppt acclimated toadfish. These results emphasize that electrogenic ion transport facilitates water-absorptive properties of the urinary bladder in Gulf toadfish - a process that is regulated to facilitate water homeostasis.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relationships between age, sex and exercise intensity on cerebral artery haemodynamics during isometric handgrip exercise.","authors":"Jodie L Koep, Bert Bond, Chloe E Taylor, Alan R Barker, Stefanie L Ruediger, Faith K Pizzey, Jeff S Coombes, Tom G Bailey","doi":"10.1152/ajpregu.00014.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00014.2024","url":null,"abstract":"<p><p>Age and sex may alter the cerebral blood flow (CBF) responses to acute isometric exercise, via associated elevations in mean arterial pressure (MAP) and sympathetic activation. Our aim was to determine the relationships between age, sex and exercise intensity on cerebrovascular responses to isometric handgrip exercise. In 78 healthy adults (18-80 years, N=42 female), cerebrovascular responses were assessed during two minute isometric exercise bouts at three intensities (15, 30, 45% maximal voluntary contraction). Intracranial responses of the middle cerebral artery (MCA) and posterior cerebral artery (PCA) velocity (v) were measured using transcranial Doppler ultrasound. Extracranial responses of the internal carotid artery (ICA) and vertebral artery (VA) were assessed using Duplex ultrasound. Cardiopulmonary haemodynamic and neural parameters were measured throughout, including muscle sympathetic nerve activity, end-tidal carbon dioxide, and MAP. There were significant positive relationships between exercise intensity and the cerebral responses of the MCAv (P<0.001) and PCAv (P=0.005). There were no effects of intensity on ICA and VA responses (P>0.05), despite intensity-dependent increases in MAP (P<0.001). The increased MCAv response to exercise was blunted with advancing age (P=0.01) with no influence of sex (P=0.86). The present study provides data on age, sex and intensity specific relationships with intracranial and extracranial cerebrovascular responses to isometric exercise. Despite similar ICA, VA, and PCA responses, MCAv responses were attenuated with advancing age during handgrip exercise with no sex dependent influence. Further, intracranial responses were intensity dependent, whereas extracranial blood flow, shear-stress and velocity responses were similarly increased at all intensities during handgrip exercise.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is muscle sympathetic nerve activity associated with cerebral blood velocity? A partial coherence analysis.","authors":"Edgar Toschi-Dias, Ricardo C Nogueira, Edna O Silva, Graziela Amaro-Vicente, Carlos E Negrão, Maria Urbana P B Rondon, Ronney B Panerai","doi":"10.1152/ajpregu.00112.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00112.2024","url":null,"abstract":"<p><p>Despite some evidence, the role of sympathetic nerve activity in the regulation of cerebral blood flow remains controversial. In humans, muscle sympathetic nervous activity (MSNA) is the only direct measure of sympathetic nerve activity that can be recorded with sufficient temporal resolution, to allow association with dynamic regulation of cerebral blood velocity (CBv). This study tested the hypothesis that MSNA is associated with the regulation of CBv at rest and during different physiological maneuvers. Nine healthy subjects underwent two sympathoexcitatory maneuvers: <i>i</i>) isometric handgrip exercise (HGR), and <i>ii</i>) cold pressor test (CPT). Mean arterial pressure (MAP, oscillometric method), CBv (transcranial Doppler ultrasound), and MSNA (microneurography) were measured continuously during experimental protocols. Ordinary and partial coherences of the MAP, CBv and MSNA time series were estimated by transfer function analysis in the low-frequency range (LF: 0.07-0.20 Hz), using MAP and MSNA as inputs and CBv as the output variable. When the influence of MSNA was taken into account, the partial coherences between MAP and CBv were considerably reduced at baseline (<i>P</i><0.01), HGR (<i>P</i>=0.02), and CPT (<i>P</i><0.01). Similarly, when the influence of MAP was taken into account, the coherence between MSNA and CBv was considerably reduced at baseline (<i>P</i><0.01), HGR (<i>P</i>=0.02), and CPT (<i>P</i>=0.01), leading to the conclusion, that MSNA was associated to dynamic regulation of CBv. Partial coherence analysis is a promising method for assessing the influence of the sympathetic nervous system on cerebral hemodynamics.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiling growth performance, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in rainbow trout lacking IGFBP-2b.","authors":"Beth M Cleveland, Ayaka Izutsu, Yuika Ushizawa, Lisa Radler, Munetaka Shimizu","doi":"10.1152/ajpregu.00209.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00209.2024","url":null,"abstract":"<p><p>Insulin-like growth factor binding proteins (IGFBP) regulate insulin-like growth factor (IGF) signaling, but IGFBP-specific functions are not well characterized in fishes. A line of rainbow trout (<i>Oncorhynchus mykiss</i>) lacking a functional IGFBP-2b was produced using gene editing and subsequent breeding to an F2 generation. This loss-of-function model (2bKO) was subjected to either continuous feeding or feed deprivation (3 wk) followed by refeeding (1 wk). During continuous feeding, the 2bKO line displayed faster specific growth rate for both body weight and fork length, higher feed intake, and reduced feed conversion ratio compared to a wild type (WT) line. However, loss of IGFBP-2b did not affect the feed deprivation or refeeding response in terms of weight loss or weight gain, respectively. Several components of the IGF/IGFBP system were affected by loss of IGFBP2b. Total serum IGF-1 in the 2bKO line was reduced to 0.5 - 0.8-fold of the WT line although the concentration of free serum IGF-1 was not affected. Gene expression differences include reduced abundance of <i>igfbp1a1</i>, <i>igfbp1b2</i>, <i>igfbp5b2</i>, and <i>igfbp6b1</i> transcripts, and elevated <i>igf2</i> and <i>igfbp6b2</i> transcripts in liver of the 2bKO line. Collectively, these findings suggest that although IGFBP-2b is a carrier of circulating IGF-1 in salmonids, the presence of IGFBP-2a and compensatory responses of other IGF/IGFBP system components support an anabolic response that improved growth performance in the loss-of-function model.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liraglutide ameliorates inflammation and fibrosis by downregulating the TLR4/MyD88/NF-κB pathway in diabetic kidney disease.","authors":"Linjing Huang, Tingting Lin, Meizhen Shi, Peiwen Wu","doi":"10.1152/ajpregu.00083.2024","DOIUrl":"10.1152/ajpregu.00083.2024","url":null,"abstract":"<p><p>Inflammation and fibrosis play important roles in diabetic kidney disease (DKD). Previous studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists had renal protective effects. However, the mechanisms are not clear. The present study explored the effect of liraglutide (LR), a GLP-1R agonist, on the downregulation of glomerular inflammation and fibrosis in DKD by regulating the Toll-like receptor (TLR)4/myeloid differentiation marker 88 (MyD88)/nuclear factor κB (NF-κB) signaling pathway in mesangial cells (MCs). In vitro, rat MCs were cultured in high glucose (HG). We found that liraglutide treatment significantly reduced the HG-mediated activation of the TLR4/MYD88/NF-κB signaling pathway, extracellular matrix (ECM)-related proteins, and inflammatory factors. A combination of TLR4 inhibitor (TAK242) and liraglutide did not synergistically inhibit inflammatory factors and ECM proteins. Furthermore, in the presence of TLR4 siRNA, liraglutide significantly blunted HG-induced expression of fibronectin protein and inflammatory factors. Importantly, TLR4 selective agonist LPS or TLR4 overexpression eliminated the improvement effects of liraglutide on the HG-induced response. In vivo, administration of liraglutide for 8 wk significantly improved the glomerular damage in streptozotocin-induced diabetic mice and reduced the expression of TLR4/MYD88/NF-κB signaling proteins, ECM protein, and inflammatory factors in renal cortex. TLR4^-/- diabetic mice showed significant amelioration in urine protein excretion rate, glomerular pathological damage, inflammation, and fibrosis. Liraglutide attenuated glomerular hypertrophy, renal fibrosis, and inflammatory response in TLR4^-/- diabetic mice. Taken together, our findings suggest that TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory response and ECM protein proliferation in DKD. Liraglutide alleviates inflammation and fibrosis by downregulating the TLR4/MYD88/NF-κB signaling pathway in MCs.<b>NEW & NOTEWORTHY</b> Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has renoprotective effect in diabetic kidney disease (DKD). In DKD, TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory responses and extracellular matrix (ECM) protein proliferation. Liraglutide attenuates renal inflammation and overexpression of ECM proteins by inhibiting TLR4/MYD88/NF-κB signaling pathway. Therefore, we have identified a new mechanism that contributes to the renal protection of GLP-1RA, thus helping to design innovative treatment strategies for diabetic patients with various complications.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R410-R422"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11483077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The independent effects of hydrostatic pressure and hypercapnic breathing during water immersion on ventilatory sensitivity and cerebrovascular reactivity.","authors":"James R Sackett, Zachary J Schlader, David Hostler, Blair D Johnson","doi":"10.1152/ajpregu.00008.2024","DOIUrl":"10.1152/ajpregu.00008.2024","url":null,"abstract":"<p><p>Head-out water immersion (HOWI) induces ventilatory and hemodynamic changes, which may be a result of hydrostatic pressure, augmented arterial CO₂ tension, or a combination of both. We hypothesized that the hydrostatic pressure and elevated CO₂ tension that occur during HOWI will contribute to an augmented ventilatory sensitivity to CO₂ and an attenuated cerebrovascular reactivity to CO₂ during water immersion. Twelve subjects [age: 24 ± 3 yr, body mass index (BMI): 25 ± 3 kg/m²] completed HOWI, waist water immersion with CO₂ (WWI + CO₂), and WWI, where a rebreathing test was conducted at baseline, 10, 30, and 60 min, and postimmersion. End-tidal pressure of carbon dioxide ([Formula: see text]), minute ventilation, expired gases, blood pressure, heart rate, and middle cerebral artery blood velocity were recorded continuously. [Formula: see text] increased throughout all visits (<i>P</i> ≤ 0.011), was similar during HOWI and WWI + CO₂ (<i>P</i> ≥ 0.264), and was greater during WWI + CO₂ versus WWI at 10, 30, and 60 min (<i>P</i> < 0.001). When HOWI vs. WWI + CO₂ were compared, the change in ventilatory sensitivity to CO₂ was different at 10 (0.59 ± 0.34 vs. 0.06 ± 0.23 L/min/mmHg; <i>P</i> < 0.001), 30 (0.58 ± 0.46 vs. 0.15 ± 0.25 L/min/mmHg; <i>P</i> < 0.001), and 60 min (0.63 ± 0.45 vs. 0.16 ± 0.34 L/min/mmHg; <i>P</i> < 0.001), whereas there were no differences between conditions for cerebrovascular reactivity to CO₂ (<i>P</i> ≥ 0.163). When WWI + CO₂ versus WWI were compared, ventilatory sensitivity to CO₂ was not different between conditions (<i>P</i> ≥ 0.642), whereas the change in cerebrovascular reactivity to CO₂ was different at 30 min (-0.56 ± 0.38 vs. -0.30 ± 0.25 cm/s/mmHg; <i>P</i> = 0.010). These data indicate that during HOWI, ventilatory sensitivity to CO₂ increases due to the hydrostatic pressure, whereas cerebrovascular reactivity to CO₂ decreases due to the combined effects of immersion.<b>NEW & NOTEWORTHY</b> Although not fully elucidated, the ventilatory and hemodynamic alterations during water immersion appear to be a result of the combined effects of immersion (i.e., elevated [Formula: see text], central hypervolemia, increased cerebral perfusion, increased work of breathing, etc.). Our findings demonstrate that an augmented ventilatory sensitivity to CO₂ during immersion may be due to the hydrostatic pressure across the chest wall, whereas an attenuated cerebrovascular reactivity to CO₂ may be due to the combined effects of immersion.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R457-R472"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11483083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}