The role of SGLT inhibition in peritoneal damage during peritoneal dialysis

• Applicant: Dr. Michael S. Balzer
• Subject Area: Nephrology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388868427

Peritoneal dialysis (PD) is an essential form of renal replacement therapy in great need for research. A major issue is the limited durability and usability of the peritoneal membrane, which is due to structural damage to the peritoneum. Therefore, peritoneal membrane preservation is of utmost importance. Damages are mostly due to glucose, which is administered intraperitoneally for its osmotic properties facilitating water and solute transport. The process of peritoneal glucotoxicity has been elucidated only insufficiently. In previous work we were able to demonstrate a deleterious role of the alpha isoform of protein kinase C (PKC) at the peritoneum, while the beta isoform inherits anti-inflammatory and anti-fibrotic properties via feedback regulation of the alpha isoform.SGLT2 inhibitors are a novel class of antidiabetics approved for human use that target sodium glucose symporters. It has been demonstrated that PKC is significantly involved in the regulation of both isoforms SGLT1 and SGLT2. Knowledge on the expression and function of human SGLTs in the context of glucotoxic damage to the peritoneal membrane during PD is scarce. Mechanistically, chronic PD resembles diabetes of the peritoneal cavity. Due to their localization and function in the apical plasma membrane of mesothelial cells, SGLTs are possibly among the first structures in contact with intraperitoneally administered glucose and play a major role in glucose uptake. We therefore would like to test the hypothesis that SGLTs are significantly involved in the mediation of glucotoxicity at the peritoneal membrane and that local pharmacological inhibition of SGLTs at the peritoneal level ameliorates membrane damage. Our experimental results will contribute to the mechanistic understanding of the development of human and murine glucotoxic peritoneal damage and might establish a potential SGLT-targeted therapy for delaying the progression of peritoneal fibrosis in an animal model of PD.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Hermann Haller