Function (Oxford, England)最新文献

{"title":"Molecular and Functional Characterization of the Peritoneal Mesothelium, a Barrier for Solute Transport.","authors":"Iva Marinovic, Maria Bartosova, Eszter Levai, Rebecca Herzog, Arslan Saleem, Zhiwei Du, Conghui Zhang, Juan Manuel Sacnun, Eleanna Pitaraki, Sotirios Sinis, Ivan Damgov, Damir Krunic, Trim Lajqi, Mohammed Al-Saeedi, J Attila Szabo, Michael Hausmann, Domonkos Pap, Klaus Kratochwill, Susanne M Krug, Sotirios G Zarogiannis, Claus Peter Schmitt","doi":"10.1093/function/zqae051","DOIUrl":"10.1093/function/zqae051","url":null,"abstract":"<p><p>Peritoneal dialysis (PD) is an increasingly needed, life-maintaining kidney replacement therapy; efficient solute transport is critical for patient outcome. While the role of peritoneal perfusion on solute transport in PD has been described, the role of cellular barriers is uncertain, the mesothelium has been considered irrelevant. We calculated peritoneal blood microvascular endothelial surface area (BESA) to mesothelial surface area (MSA) ratio in human peritonea in health, chronic kidney disease, and on PD, and performed molecular transport related gene profiling and single molecule localization microscopy in two mesothelial (MC) and two endothelial cell lines (EC). Molecular-weight dependent transport was studied in-vitro, ex-vivo and in mice. Peritoneal BESA is 1-3-fold higher than MSA across age groups, and increases with PD, while the mesothelium is preserved during the first 2 years of PD. Tight junction, transmembrane and transcytotic transporter expression are cell-type specifically expressed. At nanoscale, tight junction anchoring protein Zonula occludens-1 is more abundant and more continuously expressed along the MC than the EC. Ionic conductance is 3-fold lower across the MC than human microvascular EC, as is the permeability for creatinine, 4- and 10-kDa, but not for 70-kDa dextran. MC removal from sheep peritoneum abolishes ionic barrier function. Short term intraperitoneal LPS exposure in mice selectively affects peritoneal mesothelial integrity and increases transperitoneal solute transport. We provide molecular correlates and consistent functional evidence for the mesothelium as a barrier for peritoneal solute transport, ie, essential information on peritoneal transport modeling, and for interventions to improve PD efficiency and biocompatibility, and beyond.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Anion Exchanger-1 (Band 3) on the Red Blood Cell Membrane Accelerates Scavenging of Nitric Oxide Metabolites and Predisposes Hypertension Risks.","authors":"Li-Yang Chen, Pin-Lung Chen, Si-Tse Jiang, Hui-Lin Lee, Yen-Yu Liu, Alysa Chueh, Jing-Heng Lin, Caleb G Chen, Chung-Lieh Hung, Kate Hsu","doi":"10.1093/function/zqae052","DOIUrl":"10.1093/function/zqae052","url":null,"abstract":"<p><p>The erythrocyte membrane is highly specialized with ∼1 million anion exchanger-1 (AE1) per cell for rapid membrane permeation of HCO3-(aq), as most blood CO2(g) is carried in this hydrated anionic form. People with the GP.Mur blood type have more AE1 on their erythrocyte membrane, and they excrete CO2(g) more efficiently. Unexpectedly, GP.Mur/increased AE1 is also associated with higher blood pressure (BP). To solve this, we knocked the human GYP.Mur gene into C57BL/6J mice at 3'-UTR of GYPA to generate GPMur knock-in (KI) mice. KI of human GYP.Mur increased murine AE1 expression on the red blood cells (RBC). GPMur KI mice were naturally hypertensive, with normal kidney functions and lipid profiles. Blood NO3- [the stable nitric oxide (NO) reservoir] was significantly lower in the GPMur mice. GPMur KI also accelerated AE1-mediated NO2- influx into the RBCs and intraerythrocytic NO2-/NO processing. From tests with different categories of antihypertensives, hypertension in GPMur mice responded best to direct arterial vasodilator hydralazine, suggesting that vasodilator deficiency is the leading cause of \"GPMur/AE1-triggered hypertension.\" In conclusion, we showed that GPMur/increased AE1 predisposed hypertension risks. Mechanistically, higher AE1 expression increased RBC membrane permeability for NO2- and consequently accelerated erythroid NO2-/NO metabolism; this is associated with lower NO bioavailability and higher BP. As hypertension affects a quarter of the world population and GP.Mur is a common Southeast Asian (SEA) blood type, this work may serve as a primer for \"GPMur (biomarker)-based\" therapeutic development for hypertension.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Glucose Homeostasis Requires Pancreatic but Not Neuronal ATP-sensitive Potassium Channels.","authors":"Athena H Li, Wen-Sheng Tsai, Wen-Hao Tsai, Shi-Bing Yang","doi":"10.1093/function/zqaf002","DOIUrl":"10.1093/function/zqaf002","url":null,"abstract":"<p><p>The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits, are essential for glucose homeostasis. While the role of pancreatic KATP channels in regulating insulin secretion is well-documented, the specific contributions of neuronal KATP channels remain unclear due to challenges in precisely targeting neuronal subpopulations. In this study, we utilized a Kir6.2 conditional knockout mouse model to distinguish the roles of KATP channels in different cell types. Our findings demonstrate that deletion of neuronal KATP channels does not impair glucose homeostasis, as glucose-sensing neurons retained their responsiveness despite the absence of functional KATP channels. In contrast, the deletion of KATP channels in pancreatic β cells led to significant hyperglycemia and glucose intolerance, indicating unstable blood glucose levels under varying physiological conditions. Importantly, we showed that restoring KATP channel function exclusively in pancreatic β cells within a global Kir6.2 knockout background effectively reversed glucose regulation defects. This underscores the critical role of pancreatic KATP channels in maintaining systemic glucose homeostasis. Our results challenge the previous hypothesis that neuronal KATP channels are essential for glucose regulation, suggesting that their primary function may be neuroprotective rather than homeostatic. These findings highlight pancreatic KATP channels as key regulators of glucose balance and potential therapeutic targets for correcting glucose dysregulation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thick Ascending Limb Specific Inactivation of Myh9 and Myh10 Myosin Motors Results in Progressive Kidney Disease and Drives Sex-specific Cellular Adaptation in the Distal Nephron and Collecting Duct.","authors":"Karla L Otterpohl, Brook W Busselman, Jenna L Zimmerman, Malini Mukherjee, Claire Evans, Kelly Graber, Vedant P Thakkar, Jermaine G Johnston, Arooba Ilyas, Michelle L Gumz, Douglas C Eaton, Jeff M Sands, Kameswaran Surendran, Indra Chandrasekar","doi":"10.1093/function/zqae048","DOIUrl":"10.1093/function/zqae048","url":null,"abstract":"<p><p>Our previous work established a role for myosin motor proteins MYH9 and MYH10 in trafficking of thick ascending limb (TAL) cargoes uromodulin and Na+-K+-2Cl- cotransporter NKCC2. We have generated a TAL-specific Myh9&10 conditional knockout (Myh9&10 TAL-cKO) mouse model to determine the cell autonomous roles for MYH9&10 in TAL cargo trafficking and to understand the consequence of TAL dysfunction in adult kidney. Myh9&10 TAL-cKO mice develop progressive kidney disease with pathological tubular injury confirmed by histological changes, tubular injury markers, upregulated endoplasmic reticulum (ER) stress/unfolded protein response, and higher blood urea nitrogen and serum creatinine. However, male mice survive twice as long as female mice. We have determined this sexual dimorphism in morbidity is due to adaptation of the distal nephron and collecting duct in response to TAL dysfunction and lower NKCC2 expression. We demonstrate that this triggers a compensatory mechanism involving sex-specific cellular adaptation within the distal nephron and collecting duct to boost sodium reabsorption. While both sexes overcompensate by activating epithelial sodium channel (ENaC) expression in medullary collecting ducts resulting in hypernatremia, this is initially subdued in male Myh9&10 TAL-cKO mice through higher sodium chloride cotransporter (NCC) expression within the distal nephron. Our results indicate that compromised TAL function ultimately results in maladaptation of medullary collecting duct cells which acquire cortical-like properties including ENaC expression. This work further confirms a cell autonomous role for MYH9&10 in maintenance of NKCC2 expression in the TAL and uncover distal nephron and collecting duct adaptive mechanisms which respond to TAL dysfunction.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stuck in Traffic-Myosin Motors Ease Gridlock in the Loop.","authors":"Joshua N Curry, James A McCormick","doi":"10.1093/function/zqaf008","DOIUrl":"10.1093/function/zqaf008","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic Ductal Adenocarcinoma, β-blockers, and Antihistamines: A Clinical Trial Is Needed.","authors":"Jillian G Baker, Erica K Sloan, Kevin D G Pfleger, Peter J McCormick, Cristina Salmerón, Paul A Insel","doi":"10.1093/function/zqae050","DOIUrl":"10.1093/function/zqae050","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease.","authors":"Ga-Yeon Son, Anna Zou, Amanda Wahl, Kai Ting Huang, Saruul Zorgit, Manikandan Vinu, Fang Zhou, Larry Wagner, Youssef Idaghdour, David I Yule, Stefan Feske, Rodrigo S Lacruz","doi":"10.1093/function/zqae047","DOIUrl":"10.1093/function/zqae047","url":null,"abstract":"<p><p>Ca2+ signaling via the store-operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 [Stim1/2K14Cre(+)] in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The P2Y6 Receptor as a Potential Keystone in Essential Hypertension.","authors":"Nuria Daghbouche-Rubio, Inés Álvarez-Miguel, Victor Alejandro Flores, Jorge Rojo-Mencía, Manuel Navedo, Madeleine Nieves-Citrón, Pilar Cidad, M Teresa Pérez-García, José R López-López","doi":"10.1093/function/zqae045","DOIUrl":"10.1093/function/zqae045","url":null,"abstract":"<p><p>Essential hypertension (HT) is a highly prevalent cardiovascular disease of unclear physiopathology. Pharmacological studies suggest that purinergic P2Y6 receptors (P2ry6) play important roles in cardiovascular function and may contribute to angiotensin II (AgtII) pathophysiological effects. Here, we tested the hypothesis that functional coupling between P2ry6 and AgtII receptors mediates altered vascular reactivity in HT. For this, a multipronged approach was implemented using mesenteric vascular smooth muscle cells (VSMCs) and arteries from Blood Pressure Normal (BPN) and Blood Pressure High (BPH) mice. Differential transcriptome profiling of mesenteric artery VSMCs identified P2ry6 purinergic receptor mRNA as one of the top upregulated transcripts in BPH. P2Y receptor activation elicited distinct vascular responses in mesenteric arteries from BPN and BPH mice. Accordingly, 10 µm UTP produced a contraction close to half-maximal activation in BPH arteries but no response in BPN vessels. AgtII-induced contraction was also higher in BPH mice despite having lower AgtII receptor type-1 (Agtr1) expression and was sensitive to P2ry6 modulators. Proximity ligation assay and super-resolution microscopy showed closer localization of Agtr1 and P2ry6 at/near the membrane of BPH mice. This proximal association was reduced in BPN mice, suggesting a functional role for Agtr1-P2ry6 complexes in the hypertensive phenotype. Intriguingly, BPN mice were resistant to AgtII-induced HT and showed reduced P2ry6 expression in VSMCs. Altogether, results suggest that increased functional coupling between P2ry6 and Agtr1 may contribute to enhanced vascular reactivity during HT. In this regard, blocking P2ry6 could be a potential pharmacological strategy to treat HT.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARticularly Forceful: PAR1 Drives Glomerular Mesangial Cell Contractility.","authors":"Amanda P Waller, Kaushik Muralidharan, Bryce A Kerlin","doi":"10.1093/function/zqae044","DOIUrl":"10.1093/function/zqae044","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Neurocirculatory Control in Chronic Kidney Disease: New Evidence for Blunted Sympathetic Baroreflex and Reduced Sympathetic Transduction.","authors":"Jeann L Sabino-Carvalho, Elsa Mekonnen, Matias Zanuzzi, Sabrina Li, Xiangqin Cui, Jeanie Park","doi":"10.1093/function/zqae036","DOIUrl":"10.1093/function/zqae036","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is characterized by over-activation of the sympathetic nervous system (SNS) that increases cardiovascular risk. Whether sympathetic baroreflex sensitivity (sBRS) is impaired or intact in CKD remains under-studied and controversial. Furthermore, the downstream effect of SNS activation on blood pressure transduction has not been previously examined in CKD. We tested the hypothesis that sBRS is attenuated, while sympathetic transduction is augmented in CKD. In 18 sedentary patients with CKD stages III-IV (eGFR: 40±14 mL/min) and 13 age-matched controls (eGFR: 95±10 mL/min), beat-to-beat blood pressure (BP; finger photoplethysmography), heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest for 10-min. Weighted linear regression analysis between MSNA burst incidence and diastolic BP was used to determine the spontaneous sBRS. Sympathetic-BP transduction was quantified using signal averaging, whereby the BP response to each MSNA burst was tracked over 15 cardiac cycles and averaged to derive the peak change in BP. Compared with controls, CKD patients had an attenuated sBRS [CKD: -1.34 ± 0.59 versus CON: -2.91 ± 1.09 bursts (100 heartbeats)-1 mmHg-1; P = 0.001]. |sBRS| was significantly associated with eGFR (r = 0.69, P < 0.001). CKD patients had attenuated sympathetic-BP transduction compared to controls (0.75 ± 0.7 vs. 1.60 ± 0.8 mmHg; P = 0.010). Resting MSNA was negatively associated with sympathetic transduction (r = -0.57, P = 0.002). CKD patients exhibit impaired sBRS that may contribute to SNS overactivation and cardiovascular risk in this patient population. In addition, CKD patients had an attenuated sympathetic transduction that may counteract the vascular effects of SNS overactivation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}