# WNK Kinase Regulation of Thiazide-sensitive NaCl Transport

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $499,200

## Abstract

Project Summary
 This project is designed to overcome key obstacles in understanding how sodium chloride
reabsorption along the distal nephron is regulated by diet and disease. The work will focus on
the distal convoluted tubule and the thiazide-sensitive NaCl cotransporter, which play key roles
in determining total body potassium balance and in regulating arterial pressure. In fact, we have
recently identified this segment as comprising a `potassium switch' that modulates both blood
pressure and potassium balance through activation and inhibition of NaCl transport. The
thiazide-sensitive NaCl cotransporter is activated by low NaCl intake or low potassium intake.
Our overarching hypothesis is that WNK kinases must interact to provide full regulation of
thiazide-sensitive NaCl transporter function. We now understand much about dietary K+
transporter regulation, but we don't understand as much about how low dietary NaCl intake
regulates that protein. We have a new model suggesting that low NaCl activates the transporter
by modulating the carboxyl terminus of a key kinase, WNK4. This region is important because it
interacts with other WNKs to form a signaling complex. Here, we will examine its role using a
mouse model lacking parts of this domain. We will then determine whether angiotensin II,
activated during low NaCl intake, stimulates WNK4 directly, using another novel mouse model.
We will also determine whether variations in dietary NaCl intake signal to the distal convoluted
tubule from the lumen, by altering calcium delivery to this segment. In a second aim, we will
investigate how a second form of WNK, called KS-WNK1, interacts with WNK4 to modulate salt
transport. We will test the hypothesis that this protein has dual effects, depending on its
location in the cell, acting either to stimulate NaCl transport or to inhibit it. We will use state of
the art microscopic techniques and novel mouse models to investigate these questions.

## Key facts

- **NIH application ID:** 9972590
- **Project number:** 2R01DK051496-19A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** David Hoadley Ellison
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,200
- **Award type:** 2
- **Project period:** 1998-08-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972590

## Citation

> US National Institutes of Health, RePORTER application 9972590, WNK Kinase Regulation of Thiazide-sensitive NaCl Transport (2R01DK051496-19A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9972590. Licensed CC0.

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