# SGK Regulation of Epithelial Sodium Transport

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $362,812

## Abstract

ABSTRACT
SGK1 is a key component of the signaling machinery that regulates kidney tubule ion transport. It is under
dual regulation by aldosterone, and the master kinase mTOR, which phosphorylates a specific serine (S422)
within SGK1. The physiologically important signals that control mTOR-dependent SGK1 phosphorylation are
not clear, and the regulatory mechanisms are unknown. Our preliminary data support the idea that both
angiotensin II (Ang II) and local extracellular K+ concentration ([K+]) are important activators of SGK1, which
act through one of the multi-subunit mTOR complexes, mTORC2, to stimulate SGK1 S422 phosphorylation
and hence regulate ion transporters, particularly ENaC. The major goal of the present project is to elucidate the
molecular mechanisms underlying this regulation, and to understand its physiological implications. We will: 1:
We will first examine Ang II-stimulated selective regulation of SGK1 by mTORC2. We will identify residues
within mTORC2 components SIN1 and Rictor that are phosphorylated in response to Ang II in cultured cells
using mass spectrometry and immunoblot methods. We will then test mutants at these sites for their ability to
support mTORC2-dependent SGK1 phosphorylation. We will examine the effect of Ang II on SGK1 subcellular
localization and its interaction with mTORC2. 2: Characterize the effects of K+ on mTORC2-dependent SGK1
phosphorylation and its role in modulating ENaC and ROMK in cultured cells. Our preliminary data in cultured
CCD cells and intact collecting duct support the idea that K+ modulates mTORC2 phosphorylation of SGK1 to
regulate ENaC. We will explore both the mechanism and physiological implications of these findings in cultured
cells, and extend to ROMK. We will examine the effect of altering [K+] within the physiologic range on
mTORC2-dependent SGK1 phosphorylation and ENaC and ROMK currents in mpkCCD collecting duct cells
grown on Transwell filters. We will also perform patch clamp on these cells to look directly at channel function
in the apical membrane. We will characterize the signaling mechanisms implicated in K+ regulation of SGK1.
3: Characterize in vivo the role of mTORC2 in regulating Na+ and K+ excretion. In order to test key concepts
from our in vitro experiments, and resolve discrepancies between recent publications, we will perform a series
of in vivo experiments using pharmacologic inhibitors in WT and Rictor KO mice. We will compare the effects
of pharmacologic inhibition of mTOR on Na+ and K+ handling in WT vs. distal nephron Rictor KO mice, and
reconcile divergent results using electrolyte balance studies and patch clamp to assess ENaC and ROMK
currents. Finally, we will examine the effects of acute vs. chronic loss of mTORC2 using an inducible KO model
to compare acute and chronic Rictor deletion. These studies will shed new light on hormonal regulation of
renal ion handling, and elucidate a novel mechanism for K+ to control its own excretion through direct effec...

## Key facts

- **NIH application ID:** 9898352
- **Project number:** 5R01DK056695-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** DAVID PEARCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,812
- **Award type:** 5
- **Project period:** 2018-06-20 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898352

## Citation

> US National Institutes of Health, RePORTER application 9898352, SGK Regulation of Epithelial Sodium Transport (5R01DK056695-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898352. Licensed CC0.

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