Arginine protects against colonic barrier injury induced by long-term peritoneal dialysis

Abstract

Abstract Long-term peritoneal dialysis (PD) triggers colonic dysfunction and multiple complications, yet the underlying pathogenesis and effective therapies remain elusive. We established a long-term peritoneal dialysis fluid (PDF)-treated mice model to explore molecular alterations via untargeted gas chromatography‒mass spectrometry (GC‒MS) and the data were analysed by MetaboAnalyst 5.0. After validating features against the National Institute of Standards and Technology (NIST) library and Human Metabolome Database (HMDB) libraries, we used MetaboAnalyst 5.0 to pinpoint the key discriminating metabolites and their enriched pathways, and we found abnormal arginine metabolism was closely related to colonic dysfunction. Subsequently, liquid chromatography-tandem mass spectrometry (LC‒MS/MS) and western blotting were used to determine abnormal arginine metabolism in colonic dysfunction. Additionally, the benefits of arginine were determined in PDF-treated T84 cells and the PDF-treated mouse model, evaluated the effects by histopathological staining and western blotting. Untargeted metabolomics revealed that long-term PD disrupts multiple colonic pathways, especially the arginine pathway. LC-MS/MS confirmed a marked fall in colon arginine after long-term PDF exposure. Western blot showed the downregulation of argininosuccinatelyase (ASL) and the upregulation of arginase-1 (Arg-1). Further study found that supplementing exogenous arginine to T84 cell and to PDF-treated mice reinstated mucosal morphology, restored tight junction (TJ) proteins expression, and reversed PDF-induced epithelial-barrier injury. Long-term PD leads to the injury of colonic barrier and metabolic disturbance, especially the metabolism of arginine, and exogenous arginine supplementation rescues the colon injured by PD.