Effects of Glucose and Plasminogen Activator Inhibitor‐1 on Collagen Metabolism in the Peritoneum

Abstract

Nonphysiological solutions containing high glucose levels have been considered an important factor in the etiology of fibrotic changes in long-term continuous ambulatory peritoneal dialysis (CAPD) patients. At the same time, increased Plasminogen Activator Inhibitor (PAI)-1 secretion has been reported to correlate with fibrotic changes. We suspected that the high glucose content of peritoneal dialysis solution may induce peritoneal sclerosis via up-regulation of PAI-1 gene expression. In this study, we evaluated the effects of glucose on PAI-1 activity in peritoneal fibrosis in a rat model of CAPD. The effects of glucose on the expressions of PAI-1 and several other genes correlated with collagen metabolism were also examined in cultured rat peritoneal mesothelial cells and fibroblasts. Sprague-Dawley rats were intraperitoneally injected twice daily for 28 days with phosphate-buffered saline (PBS) (control group), PBS containing 4% glucose (glucose group), or PBS containing 4% glucose plus a PAI-1 inhibitor (PAI-1 inhibitor group). Thickening of the peritoneum with increase the deposition of collagens type I and III in the submesothelial interstitium were observed in the glucose and the PAI-1 inhibitor group, but these were less severe in the PAI-1 inhibitor group. Glucose stimulated expression of the mRNA of PAI-1, collagen type I and III, and tissue inhibitor of metalloproteinase (TIMP)-1 in fibroblasts but not in mesothelial cells. Glucose stimulated matrix metalloproteinase (MMP)-13 mRNA expression in both cell types. The PAI-1 inhibitor suppressed expression of the mRNAs induced by glucose. In conclusion, glucose induces peritoneal fibrosis, including changes in collagen metabolism, by stimulating PAI-1 expression.

Peritoneal Mesothelial Cells as a Target of Local Aldosterone Action: Upregulation of Connective Tissue Growth Factor Expression via Serum- and Glucocorticoid-Inducible Protein Kinase 1

“…Furthermore, the marked increase in CTGF levels by factors implicated in the development of peritoneal membrane fibrosis suggests its involvement in underlying pathophysiologic mechanisms [11,40] . Indeed, the expressions of collagen type 1 and 3 mRNA in RPMCs also increased directly with the addition of aldosterone, similarly to the expression in rat mesangial cells observed in recent reports [41,42] . Stimulation of CTGF synthesis is mediated via the TGF-␤ -specific Smad signaling pathway [43] .…”

Treatment of Established Peritoneal Fibrosis by Gene Transfer of Smad7 in a Rat Model of Peritoneal Dialysis

“…It has been shown that glucose induces peritoneal fibrosis by stimulating PAI-1 expression [25] , which can be blocked by anti-TGF-␤ strategies [26] . It is also known that PAI-1 is a component of ECM and a target gene of TGF-␤ because several Smad-binding boxes (CAGA) are in the PAI-1 promoter [27] .…”

Direct Aldosterone Action as a Profibrotic Factor via ROS-Mediated SGK1 in Peritoneal Fibroblasts

“…Fibroblasts were isolated from rat peritoneum as described previously for modified differential subcultures [20,21] . Briefly, rat peritoneal fibroblasts (RPFs) were obtained from the peritoneal wall of male Wistar rats weighing about 150 g by a standard trypsin/ethylenediaminetetraacetic acid (EDTA) digestion method.…”