TY - JOUR
T1 - Hypoxia induces apoptosis in SV40-immortalized rat proximal tubular cells through the mitochondrial pathways, devoid of HIF1-mediated upregulation of Bax
AU - Tanaka, Tetsuhiro
AU - Hanafusa, Norio
AU - Ingelfinger, Julie R.
AU - Ohse, Takamoto
AU - Fujita, Toshiro
AU - Nangaku, Masaomi
N1 - Funding Information:
This work was supported by Grants in Aid for Scientific Research from the Ministry of Education, Science and Culture (#13671100) and from the Japanese Ministry of Health and Welfare (H13-21th century-17). We thank Dr. Jeremy Hughes (University of Edinburgh, UK) for helpful discussions and comments. We also thank Dr. Kiyoshi Kurokawa, Dr. Toshio Miyata, and Dr. Reiko Inagi (Tokai University, Kanagawa, Japan) for many helpful advices and generous support.
PY - 2003/9/12
Y1 - 2003/9/12
N2 - Chronic hypoxia is a major contributor to tubulointerstitial injury in various renal diseases and apoptosis is apparently involved. Although many studies report hypoxia-induced apoptosis in cultured tubular cells, information has been limited in proximal tubular cells, those from the most susceptible portion of renal tubules against hypoxia. This study was to confirm a role for apoptosis in hypoxic proximal tubular cells and to investigate its association with HIF-1. Temperature-sensitive SV40-immortalized rat proximal tubular cells (IRPTCs) showed apoptosis in 21.9±2.9% by hypoxia (0.2% O2, 48h), with alterations in mitochondrial signaling such as Bcl2 and caspase-9. Bax mRNA was unaffected during the process. However, treating IRPTCs at the nonpermissive temperature showed an upregulation of Bax by hypoxia, which was abrogated by overexpressing dominant-negative HIF-1α. These findings extend previous reports on hypoxia-mediated tubular cell apoptosis and demonstrate the possible involvement of HIF-1 as an upstream molecule of Bax.
AB - Chronic hypoxia is a major contributor to tubulointerstitial injury in various renal diseases and apoptosis is apparently involved. Although many studies report hypoxia-induced apoptosis in cultured tubular cells, information has been limited in proximal tubular cells, those from the most susceptible portion of renal tubules against hypoxia. This study was to confirm a role for apoptosis in hypoxic proximal tubular cells and to investigate its association with HIF-1. Temperature-sensitive SV40-immortalized rat proximal tubular cells (IRPTCs) showed apoptosis in 21.9±2.9% by hypoxia (0.2% O2, 48h), with alterations in mitochondrial signaling such as Bcl2 and caspase-9. Bax mRNA was unaffected during the process. However, treating IRPTCs at the nonpermissive temperature showed an upregulation of Bax by hypoxia, which was abrogated by overexpressing dominant-negative HIF-1α. These findings extend previous reports on hypoxia-mediated tubular cell apoptosis and demonstrate the possible involvement of HIF-1 as an upstream molecule of Bax.
KW - Bcl2
KW - Caspase-9
KW - IRPTC
KW - p53
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U2 - 10.1016/S0006-291X(03)01557-2
DO - 10.1016/S0006-291X(03)01557-2
M3 - Article
C2 - 12943686
AN - SCOPUS:0042235096
SN - 0006-291X
VL - 309
SP - 222
EP - 231
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -