title: Combined ETA/ETB receptor blockade of human peritoneal mesothelial cells inhibits collagen I RNA synthesis.
abstract: BACKGROUND
  Peritoneal fibrosis is a serious complication of peritoneal dialysis; however, the mechanisms are poorly understood. We studied osmolarity and physical stress-induced effects on collagen I RNA synthesis in human peritoneal mesothelial cells (HPMCs) and focused on endothelin as a possible mediator.
  
  
  METHODS
  HPMCs were grown in a medium containing either d-glucose or glycerol to analyze the impact of osmolarity on mesothelial endothelin-1 (ET-1) release and on collagen I RNA synthesis [reverse transcription-polymerase chain reaction (RT-PCR)]. A cellular model of nonlaminar fluid shear stress and cellular stretch was used to analyze the effects of physical forces. To neutralize the endothelin effects, a combined ETA/ETB receptor antagonist (LU 302 872) was chosen.
  
  
  RESULTS
  Glucose, but not glycerol, increased mesothelial ET-1 release in a concentration and time-dependent manner (P < 0.05 vs. controls). Collagen I RNA synthesis was significantly higher in glucose-challenged cell cultures (P < 0.05 vs. controls). The glucose-mediated collagen I RNA synthesis was completely inhibited by adding the combined ETA/ETB receptor antagonist to the medium. Fluid shear stress, but not cellular stretch, led to a significant increase in the mesothelial ET-1 release (P < 0.005 vs. controls) and collagen I RNA synthesis (P < 0.05 vs. controls). LU 302 872 completely inhibited these effects.
  
  
  CONCLUSIONS
  We found that glucose and fluid shear stress are potent stimuli for ET-1 release and collagen I RNA synthesis in a model cellular system. Although our system is highly artificial, our findings raise the hypothesis that similar effects may occur in the peritoneal membranes of peritoneal dialysis patients and suggest that endothelin might be involved.
authors: Department of Nephrology, Charité, Humboldt University of Berlin, Berlin, Germany. stanislao.morgera@charite.de
authors: Stanislao
authors: S
authors: Morgera
authors: Juliane
authors: J
authors: Schlenstedt
authors: Pia
authors: P
authors: Hambach
authors: Markus
authors: M
authors: Giessing
authors: Serdar
authors: S
authors: Deger
authors: Berthold
authors: B
authors: Hocher
authors: Hans-Hellmut
authors: HH
authors: Neumayer
mesh_terms: D002478:Cells, Cultured; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000235:genetics; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D010537:Peritoneum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010812:Physical Stimulation; D011422:Propionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013314:Stress, Mechanical
chemical_list: D024042:Collagen Type I; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; C113044:LU 224332; D011422:Propionates; D011743:Pyrimidines; D012313:RNA; D005947:Glucose