Hypoxia induces an autocrine-paracrine survival pathway via platelet-derived growth factor (PDGF)-B/PDGF-beta receptor/phosphatidylinositol 3-kinase/Akt signaling in RN46A neuronal cells.
In neurons, hypoxia activates intracellular death-related pathways, yet the antiapoptotic mechanisms triggered by hypoxia remain unclear. In RN46A neuronal cells, minimum media growth conditions induced cell death as early as 12 h after the cells were placed in these conditions (i.e., after removal of B-27 supplement). However, apoptosis occurred in hypoxia (1% O2) only after 48 h, and in fact hypoxia reduced the apoptosis associated with trophic factor withdrawal. Furthermore, hypoxia induced time-dependent increases in expression of platelet-derived growth factor (PDGF) B mRNA and protein, as well as PDGF-beta receptor phosphorylation. Although exogenous PDGF-BB induced only transient Akt activation, hypoxia triggered persistent activation of Akt for up to 24 h. Inhibition of phosphatidylinositol 3-kinase (PI3K) or of PDGF-beta receptor phosphorylation abrogated both hypoxia-induced and exogenous PDGF-BB-induced Akt phosphorylation, and it completely abolished hypoxia-induced protection from media supplement deprivation, which suggests that the long-lasting activation of Akt during hypoxia and the prosurvival induction were due to endogenously generated PDGF-BB. Furthermore, these inhibitors decreased hypoxia-inducible factor 1alpha (HIF-1alpha) DNA binding, which suggests that the PDGF/PDGF-beta receptor/Akt pathway induces downstream HIF-1alpha gene transcription. We conclude that in RN46A neuronal cells, hypoxia activates an autocrine-paracrine antiapoptotic mechanism that involves up-regulation of PDGF-B and PDGF-beta receptor-dependent activation of the PI3K/Akt signaling pathway to induce downstream transcription of survival genes.
Zhang
Shelley X L
SX
Kosair Children's Hospital Research Institute, Department of Pediatrics, Louisville, Kentucky, USA.
Gozal
David
D
Sachleben
Leroy R
LR
Rane
Madhavi
M
Klein
Jon B
JB
Gozal
Evelyne
E
D017209:Apoptosis; D019898:Autocrine Communication; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D003470:Culture Media; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D019899:Paracrine Communication; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis
D003470:Culture Media; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta; D014157:Transcription Factors