During continuous ambulatory peritoneal dialysis, the peritoneum is directl
y and continuously exposed to unphysiologic peritoneal dialysis fluid; the
resulting mesothelial damage has been suggested to cause loss of ultrafiltr
ation and dialysis efficacy. The present study investigated the effect of a
high glucose concentration on cultured human peritoneal mesothelial cells
to clarify the cause of decreased dialysis efficacy during prolonged perito
neal dialysis. High glucose caused a concentration-dependent decrease ill c
ell proliferation, damage to the intercellular junctions, and excess produc
tion of transforming growth factor-beta (TGF-beta). The levels of intercell
ular junctional proteins (ZO-1, E-cadherin, and beta -catenin) were decreas
ed, and immuno-staining by anti-ZO-1 and anti-beta -catenin antibodies beca
me weaker and often discontinuous along the cell contour. Mannitol had simi
lar but weaker effects at the same osmolality, and an anti-TGF-beta neutral
izing antibody reduced the effects of high glucose. Therefore, these effect
s were induced not only by glucose itself but also by hyperosmolality and b
y a glucose-induced increase of TGF-beta. These findings suggest that the p
eritoneal mesothelium is damaged by prolonged peritoneal dialysis using hig
h glucose dialysate and that impairment of the intercellular junctions of p
eritoneal mesothelial cells by high glucose dialysate induces peritoneal hy
perpermeability and a progressive reduction in dialysis efficacy.