title: ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney.
abstract: OBJECTIVE
  Activin receptor-like kinase 1 (ALK1) is a transforming growth factor β (TGF-β) receptor, which is mainly expressed in endothelial cells regulating proliferation and migration in vitro and angiogenesis in vivo. Endothelial cells also express the co-receptor endoglin, which modulates ALK1 effects on endothelial cells. Our previous studies showed that mice with reduced endoglin levels develop less irradiation-induced vascular damage and fibrosis, caused by an impaired inflammatory response. This study was aimed at investigating the role of ALK1 in late radiation toxicity.
  
  
  METHODS
  Kidneys of ALK(+/+) and ALK1(+/-) mice were irradiated with 14 Gy. Mice were sacrificed at 10, 20, and 30 weeks after irradiation and gene expression and protein levels were analyzed.
  
  
  RESULTS
  Compared to wild type littermates, ALK1(+/-) mice developed less inflammation and fibrosis at 20 weeks after irradiation, but displayed an increase in pro-inflammatory and pro-fibrotic gene expression at 30 weeks. In addition, ALK1(+/-) mice showed superior vascular integrity at 10 and 20 weeks after irradiation which deteriorated at 30 weeks coinciding with changes in the VEGF pathway.
  
  
  CONCLUSIONS
  ALK1(+/-) mice develop a delayed normal tissue response by modulating the inflammatory response and growth factor expression after irradiation.
authors.affiliation: Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Scharpfenecker
authors.forename: Ben
authors.initials: B
authors.lastname: Floot
authors.forename: Regina
authors.initials: R
authors.lastname: Korlaar
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Russell
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stewart
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D000071063:Endoglin; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D006579:Heterozygote; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D030201:Activin Receptors, Type I