TY - JOUR
T1 - Albumin suppresses vascular endothelial growth factor via alteration of hypoxia-inducible factor/hypoxia-responsive element pathway
AU - Katavetin, Pisut
AU - Inagi, Reiko
AU - Miyata, Toshio
AU - Tanaka, Tetsuhiro
AU - Sassa, Ryoji
AU - Ingelfinger, Julie R.
AU - Fujita, Toshiro
AU - Nangaku, Masaomi
PY - 2008/3/7
Y1 - 2008/3/7
N2 - Reduction of vascular endothelial growth factor (VEGF) expression plays a crucial role in chronic kidney disease (CKD). In order to clarify a cause of VEGF suppression in CKD, we examined an interaction between proteinuria and VEGF. Rat proximal tubular cells were subjected to hypoxia with or without albumin to mimic proteinuric conditions, and VEGF expression was assessed by real-time quantitative PCR and enzyme-linked immunosorbent assays. Albumin significantly reduced VEGF expression under hypoxia. Luciferase activity controlled by hypoxia-responsive element (HRE) was suppressed by albumin, demonstrating suppression of the hypoxia-inducible factor (HIF)/HRE pathway. Studies utilizing a proteasome inhibitor and a prolyl hydroxylase inhibitor showed that mechanisms of HIF/HRE pathway suppression by albumin load did not involve degradation of HIF protein levels. Further, albumin did not change HIF mRNA levels. Our data, for the first time, suggest a clear 'link' between proteinuria and hypoxia, the two principal pathogenic factors for CKD progression.
AB - Reduction of vascular endothelial growth factor (VEGF) expression plays a crucial role in chronic kidney disease (CKD). In order to clarify a cause of VEGF suppression in CKD, we examined an interaction between proteinuria and VEGF. Rat proximal tubular cells were subjected to hypoxia with or without albumin to mimic proteinuric conditions, and VEGF expression was assessed by real-time quantitative PCR and enzyme-linked immunosorbent assays. Albumin significantly reduced VEGF expression under hypoxia. Luciferase activity controlled by hypoxia-responsive element (HRE) was suppressed by albumin, demonstrating suppression of the hypoxia-inducible factor (HIF)/HRE pathway. Studies utilizing a proteasome inhibitor and a prolyl hydroxylase inhibitor showed that mechanisms of HIF/HRE pathway suppression by albumin load did not involve degradation of HIF protein levels. Further, albumin did not change HIF mRNA levels. Our data, for the first time, suggest a clear 'link' between proteinuria and hypoxia, the two principal pathogenic factors for CKD progression.
KW - Albumin
KW - HIF
KW - Hypoxia
KW - Proteinuria
KW - Proximal tubule
KW - VEGF
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U2 - 10.1016/j.bbrc.2007.12.086
DO - 10.1016/j.bbrc.2007.12.086
M3 - Article
C2 - 18155159
AN - SCOPUS:38349082300
VL - 367
SP - 305
EP - 310
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -