Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent.
Ischemic acute renal failure is a frequent clinical problem in hospitalized patients and is associated with significant mortality. Hypoxia-inducible factor 1 (HIF-1) mediates cellular adaptation to hypoxia by regulating biological processes important for cell survival, which include glycolysis, angiogenesis, erythropoiesis, apoptosis, and proliferation. To investigate the role of HIF-1 in hypoxia-induced renal epithelial cell death, we generated mice that allow inactivation of HIF-1alpha by tetracycline-inducible Cre-loxP-mediated recombination in primary renal proximal tubule cells (PRPTC), resulting in a suppression of HIF-1-mediated gene transcription during oxygen deprivation. In the absence of glucose, the onset and the degree of hypoxia-induced cell death in HIF-1-deficient PRPTC were comparable to wild-type cells. However, when glucose availability was limited, the onset of cell death was delayed in either PRPTC that were HIF-1 deficient or in wild-type PRPTC when glycolysis or glucose uptake was partially inhibited. Our findings suggest in an in vitro genetic model that 1) the generation of adequate energy levels for the maintenance of PRPTC viability under hypoxia does not require HIF-1 and 2) that HIF-1 regulates the timing of hypoxia-induced cell death and apoptosis onset through its effects on glucose consumption.
Biju
Mangatt P
MP
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104-6144, USA.
Akai
Yasuhiro
Y
Shrimanker
Nikita
N
Haase
Volker H
VH
D058186:Acute Kidney Injury / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D051793:Hypoxia-Inducible Factor 1 / Q000172:deficiency / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism; D051379:Mice
D051793:Hypoxia-Inducible Factor 1; D005947:Glucose