# Regulation of Renal WNK Signaling in Intercalated Cells

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $375,445

## Abstract

The kidneys play a primary role in the maintenance of potassium homeostasis. The aldosterone sensitive distal
nephron (ASDN) regulates potassium balance by matching the rate of urinary K+ excretion with changes in
extracellular [K+]. Intercalated cells (ICs) play an important role in this process. Within these cells, apical large
conductance BK channels open in response to shear stress to facilitate flow-induced K+ secretion (FIKS), a
process activated by hyperkalemia. Though ICs mediate the transcellular movement of K+ from the peritubular
interstitium into the tubule lumen, they are unique in that their basolateral K+ entry step is not carried out by
the Na+/K+-ATPase. Instead, current evidence suggests that this process requires a bumetanide-sensitive
Na+-K+-2Cl- cotransporter, NKCC1 (SLC12A2). NKCC1 is activated via direct phosphorylation, a process
mediated by the WNK-SPAK/OSR1 pathway. Consistent with a role for this pathway in FIKS, we find that the
kinase active forms of WNK1 and SPAK are stimulated in ICs during hyperkalemia, likely to activate
basolateral NKCC1 and apical BK channels. This, however, contradicts the current paradigm, which contends
that WNK kinases should be switched off when potassium levels are high in the blood. The overall goal of this
application is to determine the importance of NKCC1 and the WNK-SPAK/OSR1 pathway in FIKS, and to test
a novel mechanism that explains how these proteins are specifically activated in ICs of the ASDN during
hyperkalemia. To accomplish this objective, we will use a variety experimental approaches, including whole
animal studies, transport measurements in isolated perfused tubules, fluorescent cell sorting and isolation of
ICs derived from whole kidney, and in vitro studies in cell culture models. The information gained from these
studies will advance our knowledge of the molecular mechanisms underlying the ASDN’s response to
potassium stress.

## Key facts

- **NIH application ID:** 10440321
- **Project number:** 5R01DK119252-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** AROHAN R SUBRAMANYA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,445
- **Award type:** 5
- **Project period:** 2019-07-23 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440321

## Citation

> US National Institutes of Health, RePORTER application 10440321, Regulation of Renal WNK Signaling in Intercalated Cells (5R01DK119252-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440321. Licensed CC0.

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