NYMC Faculty Publications

Potassium Activates Mtorc2-Dependent SGK1 Phosphorylation to Stimulate Epithelial Sodium Channel: Role in Rapid Renal Responses to Dietary Potassium

Bidisha Saha, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.
Waheed Shabbir, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.
Enzo Takagi, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.
Xin-Peng Duan, Department of Pharmacology, New York Medical College, Valhalla, New York.
Deise Carla Leite Dellova, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.
John Demko, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.
Anna Manis, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.
Dominique Loffing-Cueni, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
Johannes Loffing, Institute of Anatomy, University of Zurich, Zurich, Switzerland.
Mads Vaarby Sørensen, Department of Biomedicine, Unit of Physiology, Aarhus University, Aarhus, Denmark.
Wen-Hui Wang, Department of Pharmacology, New York Medical College, Valhalla, New York.
David Pearce, Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California.

Author Type(s)

Faculty

Journal Title

Journal of the American Society of Nephrology

First Page

1019

Last Page

1038

Document Type

Article

Publication Date

6-1-2023

Department

Pharmacology

Abstract

SIGNIFICANCE STATEMENT: Rapid renal responses to ingested potassium are essential to prevent hyperkalemia and also play a central role in blood pressure regulation. Although local extracellular K + concentration in kidney tissue is increasingly recognized as an important regulator of K + secretion, the underlying mechanisms that are relevant in vivo remain controversial. To assess the role of the signaling kinase mTOR complex-2 (mTORC2), the authors compared the effects of K + administered by gavage in wild-type mice and knockout mice with kidney tubule-specific inactivation of mTORC2. They found that mTORC2 is rapidly activated to trigger K + secretion and maintain electrolyte homeostasis. Downstream targets of mTORC2 implicated in epithelial sodium channel regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type, but not knockout, mice. These findings offer insight into electrolyte physiologic and regulatory mechanisms. 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 after a K + load by 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 Large-conductance K + (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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