CFTR Is Involved in the Fine Tuning of Intracellular Redox Status

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.

CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response

“…Unsurprisingly, the enzymatic activities of SOD, CAT, and GPx, all known to limit the production of ROS in OxS conditions (13), were decreased in the presence of Fe/Asc. However, CFTR-silenced MIN6 cells displayed lowered basal values of enzymatic activity even without the Fe/Asc challenge, a characteristic that clearly underlines the weakness of the antioxidant network in cells with decreased CFTR protein expression.…”

Hemoglobin Oxygen Affinity in Patients with Cystic Fibrosis

“…Furthermore in patients the high level of the soluble transferrin receptor [20] might be indicative for an increased red cell production and thus a reduced erythrocytic age. However, also a link between CFTR and the function of the hypoxia inducible factor has been put forward [52] which may serve as one potential reason for a lack of increased [Hb] in CF patients.…”

“…In contrast to NO glutathione is present in millimolar concentrations in the red cells [67] and binds to oxy-Hb thus shifting the curve to the left and reducing the Bohr effect [26], [68]. But a marked deficiency of extra- and intracellular glutathione possibly including erythrocytes in CF patients has been suggested [69] which might be related to the disturbed function of CFTR as glutathione transporter [52]. Very recently also an effect of glutamate on P50 was observed [70]; this substance binds to Ca ++ channel proteins in the cell membrane and may be interchanged with muscle fibres.…”

Regulation of ion transport by oxidants

“…Studies show that Cl Ϫ channels are sensitive to RS (4, 5). Cl Ϫ channels and voltage-dependent anion-selective channels in the mitochondrial membrane of the surface of bovine trachea are regulated by oxidation-reduction mechanisms (28). NO modulates CFTR expression and function in CFTR-expressing airway epithelial cells.…”