Nephrol Dial Transplant (2001) 16: 1885-1892
© 2001 European Renal Association-European Dialysis and Transplant Association
Effects of glucose dialysate on extracellular matrix production by human peritoneal mesothelial cells (HPMC): the role of TGF-ß
Department of Nephrology, Leicester General Hospital, Leicester, UK
Background. Dialysate glucose has been implicated in the loss of peritoneal membrane function seen in long-term CAPD patients.
Methods. In order to investigate this in vitro, human peritoneal mesothelial cells (HPMC) were cultured in a 50:50 mix of dialysis solution and M199 for 12 h. The dialysate was laboratory manufactured and designed to be identical in composition to PD4 (LAB). The final glucose concentration ranged between 5 and 40 mmol/l. Experiments were conducted in the presence and absence of an anti-transforming growth factor-beta (TGF-ß) antibody. Cell viability was measured by lactate dehydrogenase (LDH) release. Fibronectin (FN) and TGF-ß protein were measured by ELISA, and FN gene expression was measured by Northern analysis. Separately, the effects of recombinant TGF-ß1 added to M199: dialysate at 5 mmol/l glucose were investigated.
Results. Forty millimoles per litre d-glucose LAB caused a decrease in cell viability, as evidenced by an increase in LDH release (6.0±1.3 vs 2.6±0.7%). This effect was dependent on osmolality. Forty millimoles per litre d-glucose LAB stimulated a 15.4±4.6% increase in FN, a 46.5±18.3% increase in TGF-ß protein (both P<0.05), and 1.4±0.09-fold increase in FN mRNA compared with 5 mmol/l d-glucose LAB. Exogenous TGF-ß 0–1 ng/ml induced a dose-dependent increase in FN protein (280±45% increase at TGF-ß 1 ng/ml, P<0.0001), and FN mRNA levels (10.0±1.8-fold at TGF-ß 1 ng/ml). The increase in FN in response to 40 mmol/l glucose was significantly reduced by anti-TGF-ß antibody to levels not different from control (93.8±6.6%, P<0.05 vs no Ab).
Conclusions. These data suggest that the pro-fibrotic effect of glucose dialysate on HPMC is mediated through stimulation of TGF-ß, which promotes FN gene expression and protein production.
Keywords: CAPD; dialysis solutions; extracellular matrix proteins; glucose; mesothelial cells; TGF-ß
Correspondence and offprint requests to: Dr K. P. G. Harris, Department of Nephrology, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
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