Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma.
The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.
University Institute of Pathology, CHUV, Bugnon 25, Lausanne CH1011, Switzerland. lucienne.juillerat@chuv.hospvd.ch
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Juillerat-Jeanneret
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Celerier
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Chapuis Bernasconi
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Nguyen
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Wostl
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Maerki
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Janzer
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Corvol
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Gasc
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D015842:Serine Proteinase Inhibitors; D000808:Angiotensinogen; D012083:Renin