[HTML][HTML] AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis

I Vadász, LA Dada, A Briva, HE Trejo… - The Journal of …, 2008 - Am Soc Clin Investig
I Vadász, LA Dada, A Briva, HE Trejo, LC Welch, J Chen, PT Tóth, E Lecuona, LA Witters…
The Journal of clinical investigation, 2008Am Soc Clin Investig
Hypercapnia (elevated CO2 levels) occurs as a consequence of poor alveolar ventilation
and impairs alveolar fluid reabsorption (AFR) by promoting Na, K-ATPase endocytosis. We
studied the mechanisms regulating CO2-induced Na, K-ATPase endocytosis in alveolar
epithelial cells (AECs) and alveolar epithelial dysfunction in rats. Elevated CO2 levels
caused a rapid activation of AMP-activated protein kinase (AMPK) in AECs, a key regulator
of metabolic homeostasis. Activation of AMPK was mediated by a CO2-triggered increase in …
Hypercapnia (elevated CO2 levels) occurs as a consequence of poor alveolar ventilation and impairs alveolar fluid reabsorption (AFR) by promoting Na,K-ATPase endocytosis. We studied the mechanisms regulating CO2-induced Na,K-ATPase endocytosis in alveolar epithelial cells (AECs) and alveolar epithelial dysfunction in rats. Elevated CO2 levels caused a rapid activation of AMP-activated protein kinase (AMPK) in AECs, a key regulator of metabolic homeostasis. Activation of AMPK was mediated by a CO2-triggered increase in intracellular Ca2+ concentration and Ca2+/calmodulin-dependent kinase kinase-β (CaMKK-β). Chelating intracellular Ca2+ or abrogating CaMKK-β function by gene silencing or chemical inhibition prevented the CO2-induced AMPK activation in AECs. Activation of AMPK or overexpression of constitutively active AMPK was sufficient to activate PKC-ζ and promote Na,K-ATPase endocytosis. Inhibition or downregulation of AMPK via adenoviral delivery of dominant-negative AMPK-α1 prevented CO2-induced Na,K-ATPase endocytosis. The hypercapnia effects were independent of intracellular ROS. Exposure of rats to hypercapnia for up to 7 days caused a sustained decrease in AFR. Pretreatment with a β-adrenergic agonist, isoproterenol, or a cAMP analog ameliorated the hypercapnia-induced impairment of AFR. Accordingly, we provide evidence that elevated CO2 levels are sensed by AECs and that AMPK mediates CO2-induced Na,K-ATPase endocytosis and alveolar epithelial dysfunction, which can be prevented with β-adrenergic agonists and cAMP.
The Journal of Clinical Investigation