Transglutaminase 2 in human peritoneal dialysis-related peritoneal injury

Patients undergoing long-term peritoneal dialysis (PD) frequently develop peritoneal fibrosis and angiogenesis, leading to membrane dysfunction. Transglutaminase 2 (TG2) stabilizes the extracellular matrix against proteases. In an animal model, inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation. We investigated the expression of TG2 in 163 human peritoneal membrane tissue samples, including controls, tissues exposed to conventional acidic or low-glucose degradation product (GDP) pH-neutral solutions, and those with peritonitis or encapsulating peritoneal sclerosis (EPS), and explored the role of TG2 in high-glucose-induced pathophysiology in mesothelial cells. TG2 expression was upregulated in association with peritoneal membrane injury and was the highest in peritonitis. TG2 expression was correlated with peritoneal membrane thickness, CD68-positive macrophages, and myofibroblast expression. TG2 was expressed in mesothelial cells, α-smooth muscle actin-positive myofibroblast expression, macrophages, and endothelial cells in the diseased state. In cultured mesothelial cells, high-glucose-induced upregulation of collagen 1, TGF-β1, and TG2 was suppressed by a TG2 inhibitor or by TGF-β1 small interfering RNA. TG2 is involved in the development of peritoneal injury during PD. High-glucose dialysate is involved in the induction of peritoneal fibrosis through the interactive regulation of TGF-β and TG2. Targeting TG2 may offer therapeutic potential for managing PD complications and EPS.