mTORC2 critically regulates renal potassium handling

Grahammer F, Nesterov V, Ahmed A, Steinhardt F, Sandner L, Arnold F, Cordts T, Negrea S, Bertog M, Ruegg MA, Hall MN, Walz G, Korbmacher C, Artunc F, Huber TB (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 126

Pages Range: 1773-82

Journal Issue: 5

DOI: 10.1172/JCI80304

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-? 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 with CRIS profile

Viatcheslav Nesterov Lehrstuhl für Physiologie (Vegetative Physiologie) Marko Bertog Lehrstuhl für Physiologie (Vegetative Physiologie) Christoph Korbmacher Lehrstuhl für Physiologie (Vegetative Physiologie)

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Universität Basel CH Switzerland (CH)

How to cite

APA:

Grahammer, F., Nesterov, V., Ahmed, A., Steinhardt, F., Sandner, L., Arnold, F.,... Huber, T.B. (2016). mTORC2 critically regulates renal potassium handling. Journal of Clinical Investigation, 126(5), 1773-82. https://doi.org/10.1172/JCI80304

MLA:

Grahammer, Florian, et al. "mTORC2 critically regulates renal potassium handling." Journal of Clinical Investigation 126.5 (2016): 1773-82.

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