{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T08:57:27Z","timestamp":1768985847326,"version":"3.49.0"},"reference-count":55,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T00:00:00Z","timestamp":1699920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Slovenian Research and Innovation Agency (ARIS)","award":["#P3-0108"],"award-info":[{"award-number":["#P3-0108"]}]},{"name":"Slovenian Research and Innovation Agency (ARIS)","award":["#P1-0189"],"award-info":[{"award-number":["#P1-0189"]}]},{"name":"Slovenian Research and Innovation Agency (ARIS)","award":["#J3-2521"],"award-info":[{"award-number":["#J3-2521"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The urothelium is a vital permeability barrier that prevents the uncontrolled flow of urinary components into and out of the bladder interstitium. Our study addressed the question of possible sex-specific variations in the urothelium of healthy mice and their impact on chronic bladder inflammation. We found that healthy female bladders have a less robust barrier function than male bladders, as indicated by significant differences in transepithelial electrical resistance (TEER) values. These differences could be attributed to detected higher claudin 2 mRNA expression and a less pronounced glycocalyx in females than in males. In addition, TEER measurements showed delayed barrier recovery in chronically inflamed female bladders. We found subtle differences in the expressions of genes involved in the regulation of the actin cytoskeleton between the sexes, as well as pronounced urothelial hyperplasia in females compensating for attenuated barrier function. The identified genetic variations in glycosylation pathways may also contribute to this divergence. Our findings add to the growing body of literature on the intricate sex-specific nuances of urothelial permeability function and their implications for chronic bladder inflammation. Understanding these differences could lead to tailored diagnostic and therapeutic approaches in the treatment of bladder disorders in the future.<\/jats:p>","DOI":"10.3390\/ijms242216296","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T09:12:39Z","timestamp":1699953159000},"page":"16296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex-Dependent Differences in Blood\u2013Urine Barrier Are Subtle but Significant in Healthy and Chronically Inflamed Mouse Bladders"],"prefix":"10.3390","volume":"24","author":[{"given":"Dominika","family":"Peskar","sequence":"first","affiliation":[{"name":"Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4060-6739","authenticated-orcid":false,"given":"Mojca","family":"Kerec Kos","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3761-9945","authenticated-orcid":false,"given":"Uro\u0161","family":"Cerkvenik","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1199-4501","authenticated-orcid":false,"given":"Alenka","family":"Nemec Svete","sequence":"additional","affiliation":[{"name":"Small Animal Clinic, Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreja","family":"Erman","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1083\/jcb.111.3.1207","article-title":"Uroplakin I: A 27-kD protein associated with the asymmetric unit membrane of mammalian urothelium","volume":"111","author":"Yu","year":"1990","journal-title":"J. Cell Biol."},{"key":"ref_2","first-page":"72","article-title":"The primary antibacterial defense mechanism of the bladder","volume":"13","author":"Parsons","year":"1975","journal-title":"Investig. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0022-5347(17)39897-X","article-title":"Bladder surface glycosaminoglycans: An epithelial permeability barrier","volume":"143","author":"Parsons","year":"1990","journal-title":"J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1093\/glycob\/10.7.659","article-title":"Characterization of the rabbit homolog of human MUC1 glycoprotein isolated from bladder by affinity chromatography on immobilized jacalin","volume":"10","author":"Higuchi","year":"2000","journal-title":"Glycobiology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF01869689","article-title":"Na+ transport by rabbit urinary bladder, a tight epithelium","volume":"28","author":"Lewis","year":"1976","journal-title":"J. Membr. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nrm1055","article-title":"Signalling to and from tight junctions","volume":"4","author":"Matter","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/newbio235009a0","article-title":"Route of passive ion permeation in epithelia","volume":"235","author":"Diamond","year":"1972","journal-title":"Nat. New Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.urology.2006.03.084","article-title":"The role of the urinary epithelium in the pathogenesis of interstitial cystitis\/prostatitis\/urethritis","volume":"69","author":"Parsons","year":"2007","journal-title":"Urology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"F540","DOI":"10.1152\/ajprenal.2000.278.4.F540","article-title":"Urothelial pathophysiological changes in feline interstitial cystitis: A human model","volume":"278","author":"Lavelle","year":"2000","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00418-008-0492-x","article-title":"Rapid differentiation of superficial urothelial cells after chitosan-induced desquamation","volume":"131","author":"Veranic","year":"2009","journal-title":"Histochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature09851","article-title":"Hedgehog\/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder","volume":"472","author":"Shin","year":"2011","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.celrep.2018.09.042","article-title":"Polyploid Superficial Cells that Maintain the Urothelial Barrier Are Produced via Incomplete Cytokinesis and Endoreplication","volume":"25","author":"Wang","year":"2018","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/S0022-5347(17)38437-9","article-title":"Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis)","volume":"145","author":"Parsons","year":"1991","journal-title":"J. Urol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1097\/01.ju.0000118938.09119.a5","article-title":"Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis","volume":"171","author":"Slobodov","year":"2004","journal-title":"J. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/ncpuro0672","article-title":"Mechanisms of disease: Involvement of the urothelium in bladder dysfunction","volume":"4","author":"Birder","year":"2007","journal-title":"Nat. Clin. Pract. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"F1070","DOI":"10.1152\/ajprenal.00200.2015","article-title":"Increased urothelial paracellular transport promotes cystitis","volume":"309","author":"Montalbetti","year":"2015","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Montalbetti, N., Rued, A.C., Taiclet, S.N., Birder, L.A., Kullmann, F.A., and Carattino, M.D. (2017). Urothelial Tight Junction Barrier Dysfunction Sensitizes Bladder Afferents. eNeuro, 4.","DOI":"10.1523\/ENEURO.0381-16.2017"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1097\/01.ju.0000165170.43617.be","article-title":"Prevalence of interstitial cystitis symptoms in a managed care population","volume":"174","author":"Clemens","year":"2005","journal-title":"J. Urol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"925834","DOI":"10.3389\/fpain.2022.925834","article-title":"National prevalence of IC\/BPS in women and men utilizing veterans health administration data","volume":"3","author":"Anger","year":"2022","journal-title":"Front. Pain Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Abelson, B., Sun, D., Que, L., Nebel, R.A., Baker, D., Popiel, P., Amundsen, C.L., Chai, T., Close, C., and DiSanto, M. (2018). Sex differences in lower urinary tract biology and physiology. Biol. Sex. Differ., 9.","DOI":"10.1186\/s13293-018-0204-8"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Peskar, D., Kuret, T., Lakota, K., and Erman, A. (2023). Molecular Profiling of Inflammatory Processes in a Mouse Model of IC\/BPS: From the Complete Transcriptome to Major Sex-Related Histological Features of the Urinary Bladder. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065758"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/2211068214561025","article-title":"TEER measurement techniques for in vitro barrier model systems","volume":"20","author":"Srinivasan","year":"2015","journal-title":"J. Lab. Autom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F242","DOI":"10.1152\/ajprenal.00307.2001","article-title":"Bladder permeability barrier: Recovery from selective injury of surface epithelial cells","volume":"283","author":"Lavelle","year":"2002","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00418-013-1088-7","article-title":"Correlative study of functional and structural regeneration of urothelium after chitosan-induced injury","volume":"140","author":"Erman","year":"2013","journal-title":"Histochem. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"C1637","DOI":"10.1152\/ajpcell.1993.265.6.C1637","article-title":"Modification of epithelial permeability by cationic polypeptides","volume":"265","author":"Tzan","year":"1993","journal-title":"Am. Physiol. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.febslet.2011.01.028","article-title":"Predicted expansion of the claudin multigene family","volume":"585","author":"Mineta","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1749-6632.2009.04439.x","article-title":"Tight junction proteins as channel formers and barrier builders","volume":"1165","author":"Amasheh","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4969","DOI":"10.1242\/jcs.00165","article-title":"Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells","volume":"115","author":"Amasheh","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5509","DOI":"10.1038\/s41598-019-41971-y","article-title":"Urinary K+ promotes irritative voiding symptoms and pain in the face of urothelial barrier dysfunction","volume":"9","author":"Montalbetti","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1177\/29.9.6169760","article-title":"Primary fixation in osmium-potassium ferrocyanide: The staining of glycogen, glycoproteins, elastin, an intranuclear reticular structure, and intercisternal trabeculae","volume":"29","author":"Goldfischer","year":"1981","journal-title":"J. Histochem. Cytochem."},{"key":"ref_31","first-page":"232","article-title":"Glycosaminoglycans in the rat aorta. Ultrastructural localization with toluidine blue O and osmium--ferrocyanide procedure","volume":"105","author":"Goldfischer","year":"1981","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/BF02899062","article-title":"Cell cycle of normal bladder urothelium in developing and adult mice","volume":"57","author":"Jost","year":"1989","journal-title":"Virchows Arch. B Cell Pathol. Incl. Mol. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/ki.2009.73","article-title":"Uroplakins in urothelial biology, function, and disease","volume":"75","author":"Wu","year":"2009","journal-title":"Kidney Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nature01295","article-title":"Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity","volume":"421","author":"Speck","year":"2003","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Peskar, D., Kuret, T., Jeruc, J., and Erman, A. (2022). Lectins as Biomarkers of IC\/BPS Disease: A Comparative Study of Glycosylation Patterns in Human Pathologic Urothelium and IC\/BPS Experimental Models. Diagnostics, 12.","DOI":"10.3390\/diagnostics12051078"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3215","DOI":"10.1074\/jbc.274.5.3215","article-title":"Molecular cloning and expression of a novel beta-1, 6-N-acetylglucosaminyltransferase that forms core 2, core 4, and I branches","volume":"274","author":"Yeh","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrc1251","article-title":"Mucins in cancer: Protection and control of the cell surface","volume":"4","author":"Hollingsworth","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41585-020-0350-8","article-title":"The immune response to infection in the bladder","volume":"17","author":"Ingersoll","year":"2020","journal-title":"Nat. Rev. Urol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5197","DOI":"10.1172\/JCI138697","article-title":"Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice","volume":"130","author":"Raju","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"C897","DOI":"10.1152\/ajpcell.00282.2021","article-title":"Sex-specific adaptations to high-salt diet preserve electrolyte homeostasis with distinct sodium transporter profiles","volume":"321","author":"Ralph","year":"2021","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/S0022-5347(17)34945-5","article-title":"Bladder permeability in interstitial cystitis is similar to that of normal volunteers: Direct measurement by transvesical absorption of 99mtechnetium-diethylenetriaminepentaacetic acid","volume":"151","author":"Chelsky","year":"1994","journal-title":"J. Urol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1002\/nau.21180","article-title":"Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice","volume":"30","author":"Boudes","year":"2011","journal-title":"Neurourol. Urodyn."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e00260","DOI":"10.1002\/phy2.260","article-title":"The mouse cyclophosphamide model of bladder pain syndrome: Tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors","volume":"2","author":"Golubeva","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s004180050419","article-title":"Actin filaments during terminal differentiation of urothelial cells in the rat urinary bladder","volume":"112","author":"Romih","year":"1999","journal-title":"Histochem. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrm2866","article-title":"Organizing the cell cortex: The role of ERM proteins","volume":"11","author":"Fehon","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1242\/jcs.103.1.131","article-title":"A gene family consisting of ezrin, radixin and moesin. Its specific localization at actin filament\/plasma membrane association sites","volume":"103","author":"Sato","year":"1992","journal-title":"J. Cell Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/nau.23900","article-title":"GAG replenishment therapy for bladder pain syndrome\/interstitial cystitis","volume":"38","author":"Wyndaele","year":"2019","journal-title":"Neurourol. Urodyn."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1172\/JCI26705","article-title":"MUC1 cell surface mucin is a critical element of the mucosal barrier to infection","volume":"117","author":"McAuley","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/s41419-022-05110-2","article-title":"Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy","volume":"13","author":"Xi","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Erzar, E., Kerec Kos, M., Lakota, K., Verani\u010d, P., and Erman, A. (2020). Does the Urothelium of Old Mice Regenerate after Chitosan Injury as Quickly as the Urothelium of Young Mice?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103502"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1681\/ASN.2019040335","article-title":"Single-Cell Transcriptomic Map of the Human and Mouse Bladders","volume":"30","author":"Yu","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"W566","DOI":"10.1093\/nar\/gkv468","article-title":"ClustVis: A web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1038\/s41592-019-0582-9","article-title":"Ilastik: Interactive machine learning for (bio)image analysis","volume":"16","author":"Berg","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. 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