{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:35:11Z","timestamp":1790699711102,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T00:00:00Z","timestamp":1605744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["6205\/1-1"],"award-info":[{"award-number":["6205\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["419826430"],"award-info":[{"award-number":["419826430"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005624","name":"Medizinischen Hochschule Hannover","doi-asserted-by":"publisher","award":["intramural excellence program \u2018HiLF\u2019"],"award-info":[{"award-number":["intramural excellence program \u2018HiLF\u2019"]}],"id":[{"id":"10.13039\/501100005624","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["Research and Innovation Programme IMPROVE-PD (812699)"],"award-info":[{"award-number":["Research and Innovation Programme IMPROVE-PD (812699)"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Nephrology and Dialysis Institute","award":["(ENDI)"],"award-info":[{"award-number":["(ENDI)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Peritoneal dialysis (PD) is limited by glucose-mediated peritoneal membrane (PM) fibrosis, angiogenesis, and ultrafiltration failure. Influencing PM integrity by pharmacologically targeting sodium-dependent glucose transporter (SGLT)-mediated glucose uptake has not been studied. In this study, wildtype C57Bl\/6N mice were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of selective SGLT2 inhibitor dapagliflozin. PM structural changes, ultrafiltration capacity, and peritoneal equilibration testing (PET) status for glucose, urea, and creatinine were analyzed. Expression of SGLT and facilitative glucose transporters (GLUT) was analyzed by real-time PCR, immunofluorescence, and immunohistochemistry. Peritoneal effluents were analyzed for cellular and cytokine composition. We found that peritoneal SGLT2 was expressed in mesothelial cells and in skeletal muscle. Dapagliflozin significantly reduced effluent transforming growth factor (TGF-\u03b2) concentrations, peritoneal thickening, and fibrosis, as well as microvessel density, resulting in improved ultrafiltration, despite the fact that it did not affect development of high-glucose transporter status. In vitro, dapagliflozin reduced monocyte chemoattractant protein-1 release under high-glucose conditions in human and murine peritoneal mesothelial cells. Proinflammatory cytokine release in macrophages was reduced only when cultured in high-glucose conditions with an additional inflammatory stimulus. In summary, dapagliflozin improved structural and functional peritoneal health in the context of high-glucose PD.<\/jats:p>","DOI":"10.3390\/biom10111573","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T06:23:52Z","timestamp":1605767032000},"page":"1573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0508-1260","authenticated-orcid":false,"given":"Michael S.","family":"Balzer","sequence":"first","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9985-1515","authenticated-orcid":false,"given":"Song","family":"Rong","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Nordlohne","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.","family":"Zemtsovski","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Phenos GmbH, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1353-8064","authenticated-orcid":false,"given":"Britta","family":"Stapel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1127-3453","authenticated-orcid":false,"given":"Maria","family":"Bartosova","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University of Heidelberg, 62120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"von Vietinghoff","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Haller","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus P.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University of Heidelberg, 62120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelli","family":"Shushakova","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Phenos GmbH, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1681\/ASN.2009070694","article-title":"The pathophysiology of the peritoneal membrane","volume":"21","author":"Devuyst","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109778","DOI":"10.1016\/j.cellsig.2020.109778","article-title":"Molecular pathways in peritoneal fibrosis","volume":"75","author":"Balzer","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0022-2143(99)90113-0","article-title":"Peritoneal dialysis: Diabetes of the peritoneal cavity","volume":"134","author":"Rosenberg","year":"1999","journal-title":"J. Lab. Clin. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.kint.2016.01.025","article-title":"Protein kinase C alpha inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate","volume":"89","author":"Wang","year":"2016","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S104","DOI":"10.1038\/sj.ki.5001924","article-title":"Glucose sparing in peritoneal dialysis: Implications and metrics","volume":"70","author":"Holmes","year":"2006","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1046\/j.1523-1755.1998.00899.x","article-title":"Expression of glucose transporters in human peritoneal mesothelial cells","volume":"53","author":"Schroppel","year":"1998","journal-title":"Kidney Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.lfs.2016.07.018","article-title":"Diabetes and exposure to peritoneal dialysis solutions alter tight junction proteins and glucose transporters of rat peritoneal mesothelial cells","volume":"161","author":"Sanchez","year":"2016","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.kint.2018.05.002","article-title":"A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice","volume":"94","author":"Zhang","year":"2018","journal-title":"Kidney Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E563","DOI":"10.1152\/ajpendo.00086.2017","article-title":"Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes","volume":"313","author":"Tang","year":"2017","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12933-019-0816-2","article-title":"SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart","volume":"18","author":"Li","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.kint.2018.02.022","article-title":"Neutral pH and low-glucose degradation product dialysis fluids induce major early alterations of the peritoneal membrane in children on peritoneal dialysis","volume":"94","author":"Schaefer","year":"2018","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21344","DOI":"10.1038\/srep21344","article-title":"Quantitative Histomorphometry of the Healthy Peritoneum","volume":"6","author":"Schaefer","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1093\/ndt\/gfy282","article-title":"Protein kinase C beta deficiency increases glucose-mediated peritoneal damage via M1 macrophage polarization and up-regulation of mesothelial protein kinase C alpha","volume":"34","author":"Balzer","year":"2019","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1159\/000498965","article-title":"Involvement of STAT3 Signaling in High Glucose-Induced Epithelial Mesenchymal Transition in Human Peritoneal Mesothelial Cell Line HMrSV5","volume":"44","author":"Zhang","year":"2019","journal-title":"Kidney Blood Press. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.biopha.2018.10.106","article-title":"SGLT-2 inhibitors reduce glucose absorption from peritoneal dialysis solution by suppressing the activity of SGLT-2","volume":"109","author":"Zhou","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1681\/ASN.V1251046","article-title":"Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis","volume":"12","author":"Davies","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1046\/j.1523-1755.2001.059002463.x","article-title":"High glucose-induced PKC activation mediates TGF-beta 1 and fibronectin synthesis by peritoneal mesothelial cells","volume":"59","author":"Ha","year":"2001","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1681\/ASN.2017040436","article-title":"Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy","volume":"29","author":"Bartosova","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/pro.2858","article-title":"GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters","volume":"25","author":"Deng","year":"2016","journal-title":"Protein Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1152\/physrev.00055.2009","article-title":"Biology of human sodium glucose transporters","volume":"91","author":"Wright","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2174\/138920207780368187","article-title":"Functional properties and genomics of glucose transporters","volume":"8","author":"Zhao","year":"2007","journal-title":"Curr. Genom."},{"key":"ref_22","first-page":"103","article-title":"Regulation of glucose transporters in human peritoneal mesothelial cells","volume":"16","author":"Fischereder","year":"2003","journal-title":"J. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/315777a0","article-title":"Phosphorylation of the glucose transporter in vitro and in vivo by protein kinase C","volume":"315","author":"Witters","year":"1985","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.molcel.2015.04.015","article-title":"A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome","volume":"58","author":"Lee","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"F1017","DOI":"10.1152\/ajprenal.00021.2020","article-title":"Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney","volume":"318","author":"Hodrea","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"441","DOI":"10.3389\/fendo.2019.00441","article-title":"Dapagliflozin Attenuates Renal Tubulointerstitial Fibrosis Associated with Type 1 Diabetes by Regulating STAT1\/TGFbeta1 Signaling","volume":"10","author":"Huang","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000505144","article-title":"Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension","volume":"51","author":"Castoldi","year":"2020","journal-title":"Am. J. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.freeradbiomed.2017.01.035","article-title":"Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts","volume":"104","author":"Lee","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"F425","DOI":"10.1152\/ajprenal.1985.248.3.F425","article-title":"A distributed model of peritoneal-plasma transport: Tissue concentration gradients","volume":"248","author":"Flessner","year":"1985","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1016\/j.ekir.2020.09.003","article-title":"Novel Method for Osmotic Conductance to Glucose in Peritoneal Dialysis","volume":"5","author":"Martus","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Eich, G., Bartosova, M., Tischer, C., Wlodkowski, T.T., Schaefer, B., Pichl, S., Kraewer, N., Ranchin, B., Vondrak, K., and Liebau, M.C. (2017). Bicarbonate buffered peritoneal dialysis fluid upregulates angiopoietin-1 and promotes vessel maturation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189903"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e00239","DOI":"10.1002\/prp2.239","article-title":"Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice","volume":"4","author":"Hatanaka","year":"2016","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6305735","DOI":"10.1155\/2016\/6305735","article-title":"The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE(-\/-) Mice","volume":"2016","author":"Leng","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5335","DOI":"10.1074\/jbc.M117.779520","article-title":"SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 Protein Inhibition Decreases Renal Lipid Accumulation, Inflammation, and the Development of Nephropathy in Diabetic Mice","volume":"292","author":"Wang","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Hill, N.R., Fatoba, S.T., Oke, J.L., Hirst, J.A., O\u2019Callaghan, C.A., Lasserson, D.S., and Hobbs, F.D. (2016). Global Prevalence of Chronic Kidney Disease\u2014A Systematic Review and Meta-Analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158765"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s00125-016-4158-2","article-title":"The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE (-\/-) mice fed a western diet","volume":"60","author":"Han","year":"2017","journal-title":"Diabetologia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"F194","DOI":"10.1152\/ajprenal.00520.2013","article-title":"SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice","volume":"306","author":"Vallon","year":"2014","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ebiom.2017.05.028","article-title":"SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice","volume":"20","author":"Xu","year":"2017","journal-title":"EBioMedicine"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1573\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:34:17Z","timestamp":1760178857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,19]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["biom10111573"],"URL":"https:\/\/doi.org\/10.3390\/biom10111573","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.11.04.366724","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,19]]}}}