# Coordinated SLC12A3/SLC12A6/SL26A4 electroneutral transport pathways maintain K+ homeostasis and acid-base balance

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $692,915

## Abstract

Alkaline diets and alkalemia have a profound impact on potassium homeostasis, but the underlying
mechanisms remain poorly understood. Here we propose an innovative plan to close this significant
knowledge gap, building on our recent discovery of a long sought-after electroneutral potassium transport
pathway. Our data reveal that dietary alkaline loading stimulates the expression of the electroneutral KCl
cotransporter, KCC3a (Slc12a6), in parallel with the Cl-/HCO3- exchanger, pendrin (Slc26a4), on the B-
type intercalated cell apical membrane and the activation of the thiazide-sensitive sodium-chloride, NCC
(Slc12a3), in the Distal Convoluted Tubule. Here we advance the overarching hypothesis that KCC3a is
the long sought-after electroneutral potassium secretory pathway and propose the novel idea that coupling
between KCC3a, pendrin, and NCC maintains potassium and acid-base balance in response to the
consumption of alkaline and potassium-rich foods but drives potassium wasting in alkalosis. This new
model will be rigorously tested by a multidisciplinary team of experts, combining state-of-the-art cellular
biology and physiological phenotyping in novel genetically engineered mouse models. Aim 1 will test the
hypothesis that KCC3a is activated in response to the consumption of alkaline diets and alkalosis to drive
urinary potassium excretion. Intercalated-cell-specific KCC3 knockout mice will be investigated to a) test
the contribution of KCC3 to potassium balance and b) to pendrin-mediated HCO3- secretion; c) elucidate
the molecular mechanisms that underlie the regulation of KCC3 expression; c) test if KCC-specific
inhibitors prevent the loss of K+ in alkalemia. Aim 2 will test the hypothesis that pendrin is co-activated with
KCC3a to increase KHCO3 secretion. Pendrin knockout mice will be studied to determine: a) the
contribution of pendrin to the regulation of KCC3a; and b) the physiologic consequences of uncoupling the
transporters. We will also explore if KCC3a regulates pendrin through changes in pendrin transcription that
involve changes in intracellular chloride. Aim 3 will test the hypothesis that alkalosis drives WNK-SPAK
mediated phospho-activation of NCC to ensure electroneutral potassium bicarbonate secretion prevails
over electrogenic potassium secretion. Newly developed DCT-specific loss and gain of SPAK mice and in
vitro cell models will be examined to rigorously test this idea and explore the mechanism. In summary, this
program of investigation should illuminate a new mechanism to explain how K+ and acid-base balance are
preserved with the consumption of alkaline and potassium-rich foods, typical of the paleolithic and
vegetarian diets. The investigation is also expected to change the textbook explanation of urinary
potassium wasting in alkalosis, opening a new therapeutic horizon.

## Key facts

- **NIH application ID:** 10897951
- **Project number:** 5R01DK110375-08
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Eric J Delpire
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $692,915
- **Award type:** 5
- **Project period:** 2017-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897951

## Citation

> US National Institutes of Health, RePORTER application 10897951, Coordinated SLC12A3/SLC12A6/SL26A4 electroneutral transport pathways maintain K+ homeostasis and acid-base balance (5R01DK110375-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10897951. Licensed CC0.

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