PT  - JOURNAL ARTICLE
AU  - Michael S. Balzer
AU  - Song Rong
AU  - Johannes Nordlohne
AU  - Jan D. Zemtsovski
AU  - Sonja Schmidt
AU  - Britta Stapel
AU  - Maria Bartosova
AU  - Sibylle von Vietinghoff
AU  - Hermann Haller
AU  - Claus P. Schmitt
AU  - Nelli Shushakova
TI  - SGLT2 inhibition by intraperitoneal dapagliflozin mitigates peritoneal fibrosis and ultrafiltration failure in a mouse model of chronic peritoneal exposure to high-glucose dialysate
AID  - 10.1101/2020.11.04.366724
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.04.366724
4099  - http://biorxiv.org/content/early/2020/11/06/2020.11.04.366724.short
4100  - http://biorxiv.org/content/early/2020/11/06/2020.11.04.366724.full
AB  - 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 PET status for glucose, urea and creatinine were analyzed. Expression of SGLT and 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 TGF-β 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. Pro-inflammatory 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.Competing Interest StatementThe authors have declared no competing interest.