title: Expression and hypoxic regulation of the endothelin system in endocrine cells of human and rat pancreatic islets.
abstract: BACKGROUND
  The success of pancreatic islet transplantation depends largely on the capacity of the islet graft to survive the initial phase immediately after transplantation until revascularization is completed. Endothelin-1 (ET-1) is a strong vasoconstrictor which has been involved in solid organ graft failure but is also known to be a potent mitogenic/anti-apoptotic factor which could also potentially enhance the survival of the transplanted islets.
  
  
  OBJECTIVE
  Characterization of the endothelin system with regard to a potential endothelin agonist/antagonist treatment.
  
  
  METHODS
  Regulated expression of the endothelin system in human and rat pancreatic islets and beta-cell lines was assessed by means of immunohistochemistry, competition binding studies, western blot, RT-PCR, real-time PCR and transplant studies.
  
  
  RESULTS
  ET-1, ETA- and ETB-receptor immunoreactivity was identified in the endocrine cells of human and rat pancreatic islets. The corresponding mRNA was detectable in rat beta-cell lines and isolated rat and human pancreatic islets. Competition binding studies on rat islets revealed binding sites for both receptor types. ET-1 stimulated the phosphorylation of mitogen-activated protein kinase, which was prevented by ETA- and ETB-receptor antagonists. After exposure to hypoxia equal to post-transplant environment oxygen tension, mRNA levels of ET-1 and ETB-receptor of human islets were robustly induced whereas ETA-receptor mRNA did not show significant changes. Immunostaining signals for ET-1 and ETA-receptor of transplanted rat islets were markedly decreased when compared to native pancreatic sections.
  
  
  CONCLUSIONS
  In pancreatic islets, ET-1 and its receptors are differentially expressed by hypoxia and after transplantation. Our results provide the biological basis for the study of the potential use of endothelin agonists/antagonists to improve islet transplantation outcome.
authors.affiliation: Clinic for Visceral and Transplant Surgery, Department of Surgery, Zurich University Hospital. Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kugelmeier
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Nett
authors.forename: Richard
authors.initials: R
authors.lastname: Züllig
authors.forename: Roger
authors.initials: R
authors.lastname: Lehmann
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Moritz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3