Hypoxia induces apoptosis in SV40-immortalized rat proximal tubular cells through the mitochondrial pathways, devoid of HIF1-mediated upregulation of Bax.

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% O(2), 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-1alpha. 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.