Inhibition of the Effect of High Glucose on the Expression of Smad in Human Peritoneal Mesothelial Cells

Abstract

Objective

As high glucose (HG) concentration in peritoneal dialysis (PD) solution is thought to contribute to peritoneal fibrosis, and angiotensin II receptor blockers (ARBs) may have a key role in preventing fibrosis as they may inhibit the TGF- ß1–Smad pathway, the aims of this in vitro study were to investigate 1) if HG affects the expression of Smad in human peritoneal mesothelial cells (HPMCs) and 2) if ARB (losartan) can inhibit this effect.

Methods

HPMCs, obtained from non-renal patients undergoing elective abdominal surgery, were stimulated by HG solutions with different concentrations (1.5%, 2.5%, 4.25%) of dextrose and mannitol, and by solutions containing combination with dextrose and losartan. The supernatant was assayed for TGF- ß1 by ELISA and cells were collected for the analysis of Smad family by RT-PCR and Western Blot.

Results

1) HG up-regulated the expression of Smad2 on both gene and protein levels, especially in 2.5% and 4.25% dextrose groups (P&0.05), and also stimulated the expression of Smad4 in 4.25% dextrose group. However, the expression of Smad3 was not affected. 2) High osmolality as such (using mannitol) did not affect the TGF-ß1-Smad signaling pathway. 3) Losartan inhibited the expression of Smad2 on the gene level but not on the protein level. 4) HG up-regulated the level of TGF- ß1 with increasing dextrose concentration, while losartan partially inhibited this effect of HG on releasing of TGF-ß1.

Conclusion

A high glucose solution up-regulated the expression of Smad2 and Smad4, suggesting that the TGF- ß1-Smad pathway could be involved in the fibrosis of the peritoneum during PD. As losartan inhibited the expression of Smad2 on the gene level and reduced the concentration of TGF- ß1 in our study, the results of this in vitro study suggest that the use of angiotensin II receptor blockers might represent a possible way to prevent and treat peritoneal fibrosis in PD patients. However, further studies in vivo are needed to confirm this hypothesis.