Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells

Alveolar fluid clearance is driven by vectorial Na+ transport and promotes postnatal lung adaptation. The effect of insulin on alveolar epithelial Na+ transport was studied in isolated alveolar cells from 18–19‐day gestational age rat fetuses. Equivalent short‐circuit currents (ISC) were measured in Ussing chambers and different kinase inhibitors were used to determine the pathway of insulin stimulation. In Western Blot measurements the activation of mediators stimulated by insulin was analyzed. The ISC showed a fast dose‐dependent increase by insulin, which could be attributed to an increased ENaC (epithelial Na+ channel) activity in experiments with permeabilized apical or basolateral membrane. 5‐(N‐Ethyl‐N‐isopropyl)amiloride inhibition of ISC was not affected, however, benzamil‐sensitive ISC was increased in insulin‐stimulated monolayers. The application of LY‐294002 and Akti1/2 both completely blocked the stimulating effect of insulin on ISC. PP242 partly blocked the effect of insulin, whereas Rapamycin evoked no inhibition. Western Blot measurements revealed an increased phosphorylation of AKT after insulin stimulation. SGK1 activity was also increased by insulin as shown by Western Blot of pNDRG1. However, in Ussing chamber measurements, GSK650394, an inhibitor of SGK1 did not prevent the increase in ISC induced by insulin. The application of IGF‐1 mimicked the effect of insulin and increased the ENaC activity. In addition, an increased autophosphorylation of the IGF‐1R/IR was observed after insulin stimulation. We conclude that insulin rapidly increases epithelial Na+ transport by enhancing the activity of endogenous ENaC through activation of PI3K/AKT in alveolar cells.

• Publication year

  2014

• Venue

  Physiological Reports

• Publication date

  2014-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/phy2.269PMID 24760523PMCID 4002249
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells

  2014cited by this paper
• Regulation of ENaC in mice lacking renal insulin receptors in the collecting duct

  2013cited by this paper
• Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury

  2012influential reference
• Insulin activates epithelial sodium channel (ENaC) via phosphoinositide 3-kinase in mammalian taste receptor cells.

  2011cited by this paper
• Protein Kinase B Alpha (PKBα) Stimulates the Epithelial Sodium Channel (ENaC) Heterologously Expressed in Xenopus laevis Oocytes by Two Distinct Mechanisms

  2011influential reference
• Modulation of Sodium Transport in Alveolar Epithelial Cells by Estradiol and Progesterone

  2011cited by this paper
• Effects of nominally selective inhibitors of the kinases PI3K, SGK1 and PKB on the insulin‐dependent control of epithelial Na+ absorption

  2010cited by this paper
• Effects of peroxisome proliferator‐activated receptor γ agonists on Na+ transport and activity of the kinase SGK1 in epithelial cells from lung and kidney

  2010influential reference
• Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2

  2010cited by this paper
• Insulin regulates alveolar epithelial function by inducing Na+/K+-ATPase translocation to the plasma membrane in a process mediated by the action of Akt

  2010cited by this paper
• SGK1 activity in Na+ absorbing airway epithelial cells monitored by assaying NDRG1-Thr346/356/366 phosphorylation

  2009influential reference
• Expression of Airway Epithelial Sodium Channel in the Preterm Infant Is Related to Respiratory Distress Syndrome but Unaffected by Repeat Antenatal β-Methasone

  2009cited by this paper
• mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1).

  2008influential reference
• Ontogenèse de la régulation glycémique et conséquences pour la prise en charge du nouveau-né

  2008cited by this paper
• REGULATION OF EPITHELIAL Na+ CHANNELS BY ALDOSTERONE: ROLE OF Sgk1

  2008influential reference
• [Ontogenesis of glucose regulation in neonate and consequences in neonatal management].

  2008cited by this paper
• Trafficking of ENaC subunits in response to acute insulin in mouse kidney.

  2007influential reference
• The selectivity of protein kinase inhibitors: a further update.

  2007influential reference
• Akt Mediates the Effect of Insulin on Epithelial Sodium Channels by Inhibiting Nedd4-2*

  2007influential reference
• Signalling to translation: how signal transduction pathways control the protein synthetic machinery.

  2007cited by this paper
• Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides.

  2006cited by this paper
• SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.

  2006cited by this paper
• Insulin-induced phosphorylation of ENaC correlates with increased sodium channel function in A6 cells.

  2005influential reference
• Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex

  2005influential reference
• Identification of different specificity requirements between SGK1 and PKBα

  2005influential reference
• Low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress.

  2004cited by this paper
• Expression of epithelial sodium channel alpha-subunit mRNAs with alternative 5'-untranslated regions in the developing human lung.

  2004cited by this paper
• Modulation of sodium transport in fetal alveolar epithelial cells by oxygen and corticosterone.

  2003cited by this paper
• Insulin-stimulated trafficking of ENaC in renal cells requires PI 3-kinase activity.

  2003influential reference
• Amiloride-sensitive sodium current in everted Ambystoma initial collecting tubule: short-term insulin effects.

  2002cited by this paper
• Diabetes worsens pulmonary diffusion in heart failure, and insulin counteracts this effect.

  2002cited by this paper
• Anionic Phospholipids Regulate Native and Expressed Epithelial Sodium Channel (ENaC)*

  2002cited by this paper
• Insulin improves alveolar-capillary membrane gas conductance in type 2 diabetes.

  2002cited by this paper
• Na,K-ATPase gene transfer mitigates an oxidant-induced decrease of active sodium transport in rat fetal ATII cells.

  2001cited by this paper
• Modification of biophysical properties of lung epithelial Na(+) channels by dexamethasone.

  2000cited by this paper
• In vivo phosphorylation of the epithelial sodium channel.

  1998influential reference
• Mechanism of activation of protein kinase B by insulin and IGF‐1.

  1996cited by this paper
• Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice.

  1996influential reference
• Functional significance of the beta-subunit for heterodimeric P-type ATPases.

  1995influential reference
• Lung epithelial Na channel subunits are differentially regulated during development and by steroids.

  1995cited by this paper
• Effects of insulin and tyrosine kinase inhibitor on ion transport in the alveolar cell of the fetal lung.

  1992cited by this paper
• Growth of distal fetal rat lung epithelial cells in a defined serum-free medium

  1991cited by this paper
• Amiloride impairs lung water clearance in newborn guinea pigs.

  1990influential reference
• Insulin and IGF I receptor-mediated Na+ transport in toad urinary bladders.

  1989influential reference
• Tissue-specific and developmental regulation of rat Na,K-ATPase catalytic alpha isoform and beta subunit mRNAs.

  1988cited by this paper
• Basolateral potassium channel in turtle colon. Evidence for single-file ion flow

  1983cited by this paper

• Rosuvastatin Enhances Alveolar Fluid Clearance in Lipopolysaccharide-Induced Acute Lung Injury by Activating the Expression of Sodium Channel and Na,K-ATPase via the PI3K/AKT/Nedd4-2 Pathway

  2021cites this paper
• Development and Functional Characterization of Fetal Lung Organoids

  2021cites this paper
• Insulin regulates Nedd4-2 via a PKB-dependent mechanism in HEI-OC1 auditory cells-crosstalks with sphingolipid and cAMP signaling

  2021cites this paper
• An increase in alveolar fluid clearance induced by hyperinsulinemia in obese rats with LPS-induced acute lung injury.

  2020cites this paper
• Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide-induced acute lung injury

  2018cites this paper
• Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

  2018cites this paper
• Protectin DX increases alveolar fluid clearance in rats with 2 lipopolysaccharide-induced acute lung injury

  2017cites this paper
• Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway

  2017cites this paper
• Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone

  2017cites this paper
• University of Birmingham Protectin DX increases alveolar fluid clearance in rats with 2 lipopolysaccharide-induced acute lung injury

  2017cites this paper
• Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells

  2014cites this paper