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 ( Rictor~(fl/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, Rictor~(fl/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 Rictor~(fl/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 Ba~(2+)-sensitive apical K~(+) currents were barely detectable in the majority of Rictor~(fl/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.
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