期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 5, 页码 1773-1782出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI80304
关键词
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资金
- German Research Foundation: Collaborative Research Centres (CRC) [1140, CRC 992]
- Heisenberg program
- European Research Council [616891]
- Bundesministerium fur Bildung und Forschung-Joint Transnational Grant [01KU1215]
- Else-Kroner Fresenius Stiftung-Nierenfunktionsstorungen als Komplikation von Systemerkrankungen
- Excellence Initiative of the German federal government [EXC294]
- Excellence Initiative of the German state government (EXC294) [EXC294]
- European Research Council (ERC) [616891] Funding Source: European Research Council (ERC)
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, 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-alpha 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.
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