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Potassium Activates mTORC2-dependent SGK1 Phosphorylation to Stimulate ENaC: Role in Rapid Renal Responses to Dietary Potassium


Saha, Bidisha; Shabbir, Waheed; Takagi, Enzo; Duan, Xin-Peng; Almeida Leite Dellova, Deise Carla; Demko, John; Manis, Anna; Loffing-Cueni, Dominique; Loffing, Johannes; Sørensen, Mads Vaarby; Wang, Wen-Hui; Pearce, David (2023). Potassium Activates mTORC2-dependent SGK1 Phosphorylation to Stimulate ENaC: Role in Rapid Renal Responses to Dietary Potassium. Journal of the American Society of Nephrology (JASN), 34(6):1019-1038.

Abstract

BACKGROUND: Increasing evidence implicates the signaling kinase mTOR complex-2 (mTORC2) in rapid renal responses to changes in plasma potassium concentration [K+]. However, the underlying cellular and molecular mechanisms that are relevant in vivo for these responses remain controversial.

METHODS: We used Cre-Lox-mediated knockout of rapamycin-insensitive companion of TOR (Rictor) to inactivate mTORC2 in kidney tubule cells of mice. In a series of time-course experiments in wild-type and knockout mice, we assessed urinary and blood parameters and renal expression and activity of signaling molecules and transport proteins following a K+ load via gavage.

RESULTS: A K+ load rapidly stimulated epithelial sodium channel (ENaC) processing, plasma membrane localization, and activity in wild-type but not in knockout mice. Downstream targets of mTORC2 implicated in ENaC regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type but not knockout mice. We observed differences in urine electrolytes within 60 minutes, and plasma [K+] was greater in knockout mice within 3 hours of gavage. Renal outer medullary potassium (ROMK) channels were not acutely stimulated in wild-type or knockout mice, nor were phosphorylation of other mTORC2 substrates (PKC and Akt).

CONCLUSIONS: The mTORC2-SGK1-Nedd4-2-ENaC signaling axis is a key mediator of rapid tubule cell responses to increased plasma [K+] in vivo. The effects of K+ on this signaling module are specific, in that other downstream mTORC2 targets such as PKC and Akt are not acutely affected, and ROMK and BK channels are not activated. These findings provide new insight into the signaling network and ion transport systems that underlie renal responses to K+in vivo.

Abstract

BACKGROUND: Increasing evidence implicates the signaling kinase mTOR complex-2 (mTORC2) in rapid renal responses to changes in plasma potassium concentration [K+]. However, the underlying cellular and molecular mechanisms that are relevant in vivo for these responses remain controversial.

METHODS: We used Cre-Lox-mediated knockout of rapamycin-insensitive companion of TOR (Rictor) to inactivate mTORC2 in kidney tubule cells of mice. In a series of time-course experiments in wild-type and knockout mice, we assessed urinary and blood parameters and renal expression and activity of signaling molecules and transport proteins following a K+ load via gavage.

RESULTS: A K+ load rapidly stimulated epithelial sodium channel (ENaC) processing, plasma membrane localization, and activity in wild-type but not in knockout mice. Downstream targets of mTORC2 implicated in ENaC regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type but not knockout mice. We observed differences in urine electrolytes within 60 minutes, and plasma [K+] was greater in knockout mice within 3 hours of gavage. Renal outer medullary potassium (ROMK) channels were not acutely stimulated in wild-type or knockout mice, nor were phosphorylation of other mTORC2 substrates (PKC and Akt).

CONCLUSIONS: The mTORC2-SGK1-Nedd4-2-ENaC signaling axis is a key mediator of rapid tubule cell responses to increased plasma [K+] in vivo. The effects of K+ on this signaling module are specific, in that other downstream mTORC2 targets such as PKC and Akt are not acutely affected, and ROMK and BK channels are not activated. These findings provide new insight into the signaling network and ion transport systems that underlie renal responses to K+in vivo.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:June 2023
Deposited On:04 Apr 2023 12:24
Last Modified:30 May 2024 01:40
Publisher:American Society of Nephrology
ISSN:1046-6673
OA Status:Green
Publisher DOI:https://doi.org/10.1681/ASN.0000000000000109
PubMed ID:36890646
  • Content: Published Version
  • Language: English