Effects of glucose and plasminogen activator inhibitor-1 on collagen metabolism in the peritoneum.
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.
Higuchi
Chieko
C
Division of Internal Medicine, Tokyo Women's Medical University Daini Hospital, Tokyo, Japan. chiekogm@dnh.twmu.ac.jp
Tanihata
Yoko
Y
Nishimura
Hideki
H
Naito
Takashi
T
Sanaka
Tsutomu
T
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D017364:Collagenases / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D053509:Matrix Metalloproteinase 13; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000494:pharmacology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics
D024042:Collagen Type I; D024061:Collagen Type III; D017395:Plasminogen Activator Inhibitor 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D012313:RNA; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D005947:Glucose