Glucose and mechanical forces have been shown to be potent stimuli for mesothelial endothelin-1 release promoting profibrotic processes during peritoneal dialysis. We studied the osmolarity-induced and physical stress-induced effects on transforming growth factor-beta1 (TGF-beta1) release in human peritoneal mesothelial cells (HPMC), and analyzed whether a combined endothelin-A/endothelin-B receptor antagonist is able to mitigate HPMC TGF-beta1 release. D-Glucose and glycerol were used to analyze the impact of osmolarity on HPMC TGF-beta1 release. A cellular model of non-laminar fluid shear stress and cellular stretch was used to analyze the effects of physical forces. To neutralize the endothelin effects, a combined endothelin-A/endothelin-B receptor antagonist (LU 302 872) was chosen. Glucose, but not glycerol, increased mesothelial TGF-beta1 release in a concentration-dependent and time-dependent manner (P < 0.05 versus controls). Mechanical forces alone had no effect on mesothelial TGF-beta release. Combining fluid shear stress with high glucose medium led to a 30% increase (P = 0.019), and cellular stretch to a 34% increase (P = 0.075) in TGF-beta release compared with glucose stress alone. The combined endothelin-A/endothelin-B receptor antagonist had no impact on the mesothelial TGF-beta release. In conclusion, HPMC TGF-beta1 release by glucose and mechanical stress seems not to be related to the activity of the peritoneal endothelin system - at least in our in vitro model.