The role of protein kinase C zeta in the Na,K-ATPase regulation in alveolar epithelial cells during hypoxia

• Applicant: Dr. Markus Queisser
• Subject Area: Cell Biology
• Term: from 2010 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 185225733

The lung is essential for gas exchange between air and blood. The lung epithelium is covered of a thin layer of fluid, which is responsible for maintenance of surface tension and normal gas exchange. Acute lung injury develops due to diverse causes where the alveolo-capillary interface is disturbed, leading to fluid accumulation in the alveolar space. Fluid accumulation leads to a life-threatening im-pairment of gas exchange; therefore, clearing the excess alveolar liquid from the alveoli is of critical importance. The primary force driving fluid reabsorption from the alveoli into the pulmonary circulation is active Na+-transport. Sodium is taken up at the surface of the alveolar epithelium by Na+ channels and is subsequently pumped out of the cell by the Na,K-ATPase. The ion transport creates a gradient across the epithelium, which allows the flux of fluid out of the alveolar space. During acute lung injury, alveolar hypoxia develops due to the impaired oxygen transport from the alveoli into to the blood. Hypoxia inhibits Na,K-ATPase activity by inducing its degradation, resulting in decreased fluid clearance. Protein kinase C zeta (PKC zeta) directly phosphorylates the Na,K-ATPase triggering its removal from the plasma membrane. However, Na,KATPase degradation is limited its levels stabilize after some time of hypoxia. We speculate that Na,K-ATPase stabilization is an adaptation mechanism that is due to the degradation of PKC zeta. In this study, we will determine whether PKC zeta is degraded by the ubiquitin-proteasome system during hypoxia, we will identify the ubiquitin-ligase, which is responsible for the ubiquitination of PKC zeta and we will test its significance in animals. The completion of the aims will provide a better understanding of the regulation of active Na+-transport, which may lead to therapeutic strategies to improve fluid clearance in patients with acute lung injury.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Jacob I. Sznajder