title: mTORC2 critically regulates renal potassium handling.
abstract: The mTOR pathway orchestrates cellular homeostasis. The rapamycin-sensitive mTOR complex (mTORC1) in the kidney has been widely studied; however, mTORC2 function in renal tubules is poorly characterized. Here, we generated mice lacking mTORC2 in the distal tubule (Rictorfl/fl Ksp-Cre mice), which were viable and had no obvious phenotype, except for a 2.5-fold increase in plasma aldosterone. Challenged with a low-Na+ diet, these mice adequately reduced Na+ excretion; however, Rictorfl/fl Ksp-Cre mice rapidly developed hyperkalemia on a high-K+ diet, despite a 10-fold increase in serum aldosterone levels, implying that mTORC2 regulates kaliuresis. Phosphorylation of serum- and glucocorticoid-inducible kinase 1 (SGK1) and PKC-α was absent in Rictorfl/fl Ksp-Cre mice, indicating a functional block in K+ secretion activation via ROMK channels. Indeed, patch-clamp experiments on split-open tubular segments from the transition zone of the late connecting tubule and early cortical collecting duct demonstrated that Ba2+-sensitive apical K+ currents were barely detectable in the majority of Rictorfl/fl Ksp-Cre mice. Conversely, epithelial sodium channel (ENaC) activity was largely preserved, suggesting that the reduced ability to maintain K+ homeostasis is the result of impaired apical K+ conductance and not a reduced electrical driving force for K+ secretion. Thus, these data unravel a vital and nonredundant role of mTORC2 for distal tubular K+ handling.
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.forename: Viatcheslav
authors.initials: V
authors.lastname: Nesterov
authors.forename: Azaz
authors.initials: A
authors.lastname: Ahmed
authors.forename: Frederic
authors.initials: F
authors.lastname: Steinhardt
authors.forename: Lukas
authors.initials: L
authors.lastname: Sandner
authors.forename: Frederic
authors.initials: F
authors.lastname: Arnold
authors.forename: Tomke
authors.initials: T
authors.lastname: Cordts
authors.forename: Silvio
authors.initials: S
authors.lastname: Negrea
authors.forename: Marko
authors.initials: M
authors.lastname: Bertog
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Ruegg
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Christoph
authors.initials: C
authors.lastname: Korbmacher
authors.forename: Ferruh
authors.initials: F
authors.lastname: Artunc
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
mesh_terms: D000818:Animals; D006947:Hyperkalemia / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000502:physiology*
chemical_list: C510693:Kcnj1 protein, mouse; D046912:Multiprotein Complexes; D024661:Potassium Channels, Inwardly Rectifying; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D011188:Potassium