The Role of HIF-1α in Transcriptional Regulation of the Proximal Tubular Epithelial Cell Response to Hypoxia *

摘要: Epithelial cells of the kidney represent a primary target for hypoxic injury in ischemic acute renal failure (ARF); however, underlying transcriptional mechanism(s) remain undefined. In this study, human proximal tubular epithelial (HK-2) exposed to hypoxia vitro demonstrated non-lethal but dysfunctional phenotype, closely reflective pathobiology ARF. HK-2 increased paracellular permeability, decreased proliferation, loss tight junctional integrity, and significant actin disassembly absence cell death. Microarray analysis transcriptomic changes response identified distinct cohort 48 genes with shared hypoxia-dependent expression profile. Within hypoxia-sensitive cluster were previously as hypoxia-inducible factor-1 (HIF-1)-dependent (e.g. vascular endothelial growth factor adrenomedullin) well not known be hypoxia-responsive stanniocalcin 2). hypoxia, HIF-1 bound evolutionarily conserved hypoxia-response elements (HRE) promoters these HRE consensus motif. A further subset genes, associated regulation by HIF-1, was also present, suggesting alternative HIF-1-independent pathways. Overexpression HIF-1α normoxia induced number genes; it did induce pathophysiologic response. summary, hypoxia-elicited alterations resemble pathophysiology Our data indicate that although event may rely heavily on HIF-1-dependent gene transcription, is likely separate regulators play role.