Angiotensin II stimulates hypoxia-inducible factor 1alpha accumulation in glomerular mesangial cells.
Hypoxia increases hypoxia-inducible factor 1alpha (HIF-1alpha) protein levels by inhibiting ubiquitination and degradation of HIF-1alpha, which regulates the transcription of many genes. Recent studies have revealed that many ligands can stimulate HIF-1alpha accumulation under nonhypoxic conditions. In this study, we show that angiotensin II (Ang II) increased HIF-1alpha protein levels in a time- and dose-dependent manner under normoxic conditions. Treatment of mesangial cells with Ang II (100 nM) increased production of reactive oxygen species (ROS). Ang II (100 nM) increased the phosphorylation of PDK-1 and Akt/PKB in glomerular mesangial cells. Ang II-stimulated HIF-1alpha accumulation was blocked by the phosphatidylinositol 3-kinase (PI-3K) inhibitors, Ly 294001, and wortmannin, suggesting that PI-3K was involved. Because increased ROS generation by Ang II may activate the PI-3K-PKB/Akt signaling pathway, these results suggest that Ang II may stimulate a ROS-dependent activation of the PI-3K-PKB/Akt pathway, which leads to HIF-1alpha accumulation.
Chen
Tso-Hsiao
TH
Department of Internal Medicine, Taipei Medical University-Wan-Fang Hospital, Taiwan.
Wang
Jin-Fong
JF
Chan
Paul
P
Lee
Horng-Mo
HM
D000804:Angiotensin II / Q000494:pharmacology*; D002460:Cell Line; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases