CFTR is involved in the fine tuning of intracellular redox status: physiological implications in cystic fibrosis

Am J Pathol. 2012 Oct;181(4):1367-77. doi: 10.1016/j.ajpath.2012.06.017. Epub 2012 Jul 28.

Abstract

Adaptation to hypoxia is an essential physiological response to decrease in tissue oxygenation. This process is primarily under the control of transcriptional activator hypoxia-inducible factor (HIF1). A better understanding of the intracellular HIF1 stabilization pathway would help in management of various diseases characterized by anemia. Among human pathologies, cystic fibrosis disease is characterized by a chronic anemia that is inadequately compensated by the classical erythroid response mediated by the HIF pathway. Because the kidney expresses CFTR and is a master organ involved in the adaptation to hypoxia, we used renal cells to explore the relationship between CFTR and the HIF1-mediated pathway. To monitor the adaptive response to hypoxia, we engineered a hypoxia-induced fluorescent reporter system to determine whether CFTR modulates hypoxia-induced HIF1 stabilization. We show that CFTR is a regulator of HIF stabilization by controlling the intracellular reactive oxygen species (ROS) level through its ability to transport glutathione (a ROS scavenger) out of the cell. Moreover, we demonstrated in a mouse model that both the pharmacological inhibition and the ΔF508 mutation of CFTR lead to an impairment of the adaptive erythroid response to oxygen deprivation. We conclude that CFTR controls HIF stabilization through control of the level of intracellular ROS that act as signaling agents in the HIF-1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Carbonic Anhydrases / metabolism
  • Cell Hypoxia / drug effects
  • Cell Line
  • Chloride Channels / metabolism
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / physiopathology*
  • Cystic Fibrosis / urine
  • Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Disease Models, Animal
  • Glutathione / metabolism
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism*
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Mutation / genetics
  • Osmolar Concentration
  • Oxidation-Reduction / drug effects
  • Protein Stability / drug effects
  • Protein Structure, Tertiary
  • Reactive Oxygen Species / metabolism

Substances

  • Chloride Channels
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Green Fluorescent Proteins
  • Carbonic Anhydrases
  • Glutathione
  • Acetylcysteine