Peritoneal Expression of SGLT-2, GLUT1, and GLUT3 in Peritoneal Dialysis Patients

Abstract

Introduction: In peritoneal dialysis (PD) patients, the peritoneal membrane is affected by glucose-based solutions used as peritoneal dialysate fluids. This exposure leads to changes of the membrane which may eventually culminate in fibrosis and method failure. In vitro or animal studies demonstrated that glucose transporters are upregulated upon exposure to these solutions. Expression studies of glucose transporters in human peritoneum have not been reported yet. Methods: Expression of SGLT-2, GLUT1, and GLUT3 in human peritoneal biopsies was analyzed by real-time polymerase chain reaction and Western blot analysis. The localization of these glucose transporters in the peritoneum was evaluated by immunohistochemistry using a Histo-Score. Results: Peritoneal biopsies of patients (healthy controls, uremic, PD, and encapsulating peritoneal sclerosis [EPS]) were analyzed. We found evidence of SGLT-2, GLUT1, and GLUT3 expression in the peritoneal membrane. Protein expression of SGLT-2 increases with PD duration and is significantly enhanced in EPS patients. All transporters were predominantly, but not exclusively, located adjacent to the vessel walls of the peritoneal membrane. Conclusion: Our study showed that SGLT-2, GLUT1, and GLUT3 were regularly expressed in the human peritoneum. SGLT-2 was particularly upregulated in PD patients with EPS, suggesting that this upregulation may be associated with pathological changes in the peritoneal membrane in this syndrome. Since preclinical studies in mice show that SGLT-2 inhibitors or downregulation of SGLT-2 ameliorated pathological changes in the peritoneum, SGLT-2 inhibitors may be potentially promising agents for therapy in PD patients that could reduce glucose absorption and delay functional deterioration of the peritoneal membrane in the long term.

Enhanced Oxidative DNA-Damage in Peritoneal Dialysis Patients via the TXNIP/TRX Axis

“…Peritoneal biopsy lysates were prepared as previously described [ 28 ]. TRX activity of 20 µg protein samples was analyzed using the fluorescence-based assay kit (FkTRX-04, BIOZOL, Eching, Germany) according to the manufacturer’s instructions.…”

“…Peritoneal biopsies were formalin-fixed in 4% buffered formalin and paraffin-embedded following routine protocols [ 29 ]. Immunohistochemistry was performed as previously described [ 28 , 30 , 31 ]. Used antibodies: anti-TXNIP (ab188865; 1:200, Abcam, Cambridge, UK), anti-TRX (sc-271281; 1:100, Santa Cruz), anti- γH2AX (9718S; 1:100, CST).…”

“…Immunohistochemistry results were semi-quantitatively evaluated as previously described [ 28 , 32 ]. The following structures or cells of these structures were analyzed: mesothelial structure, submesothelial structure, adipocytes and vessels.…”

The Peritoneal Membrane—A Potential Mediator of Fibrosis and Inflammation among Heart Failure Patients on Peritoneal Dialysis

“…The authors therefore conclude that SGLT-2 inhibitors may have potential therapeutic benefit among PD patients. These drugs may reduce glucose absorption through the peritoneal membrane and delay the long-term deleterious effects of glucose on the transport function of the peritoneal membrane, thus prolonging its use and perhaps preventing EPS [ 44 ].…”

The Sweet Science of Glucose Transport

“…There have been a limited number of studies exploring GLUT expression in the peritoneum. Studies in human peritoneal mesothelial cells have demonstrated expression of GLUT1, GLUT3, SGLT1, and even SGLT2, although results have been inconsistent among studies 4 – 6 . Exposure to high-glucose solutions in cell culture and animal models has also been demonstrated to upregulate GLUT expression, but again, results have varied across studies 4 …”