title: mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity.
abstract: The epithelial Na+ channel (ENaC) is essential for Na+ homeostasis, and dysregulation of this channel underlies many forms of hypertension. Recent studies suggest that mTOR regulates phosphorylation and activation of serum/glucocorticoid regulated kinase 1 (SGK1), which is known to inhibit ENaC internalization and degradation; however, it is not clear whether mTOR contributes to the regulation of renal tubule ion transport. Here, we evaluated the effect of selective mTOR inhibitors on kidney tubule Na+ and K+ transport in WT and Sgk1-/- mice, as well as in isolated collecting tubules. We found that 2 structurally distinct competitive inhibitors (PP242 and AZD8055), both of which prevent all mTOR-dependent phosphorylation, including that of SGK1, caused substantial natriuresis, but not kaliuresis, in WT mice, which indicates that mTOR preferentially influences ENaC function. PP242 also substantially inhibited Na+ currents in isolated perfused cortical collecting tubules. Accordingly, patch clamp studies on cortical tubule apical membranes revealed that mTOR inhibition markedly reduces ENaC activity, but does not alter activity of K+ inwardly rectifying channels (ROMK channels). Together, these results demonstrate that mTOR regulates kidney tubule ion handling and suggest that mTOR regulates Na+ homeostasis through SGK1-dependent modulation of ENaC activity.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Gleason
authors.forename: Gustavo
authors.initials: G
authors.lastname: Frindt
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Michael
authors.initials: M
authors.lastname: Ng
authors.forename: Atif
authors.initials: A
authors.lastname: Kidwai
authors.forename: Priyanka
authors.initials: P
authors.lastname: Rashmi
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Michel
authors.initials: M
authors.lastname: Baum
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Palmer
authors.forename: David
authors.initials: D
authors.lastname: Pearce
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D017874:Immediate-Early Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008564:Membrane Potentials; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology*; D000075702:Nedd4 Ubiquitin Protein Ligases; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000584:Amiloride; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D007211:Indoles; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D020123:Sirolimus; D012964:Sodium; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C546843:mTOR protein, mouse; C572919:PP242