# The molecular and physiologic effects of calcineurin inhibitors on WNK body bimolecular condensates

> **NIH DK R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2026 · $769,882

## Abstract

ABSTRACT
The U.S. recently reached a historic milestone, surpassing one million life-saving organ transplants. For these
patients, tacrolimus—a calcineurin inhibitor (CNI)—is the cornerstone of immunosuppression, prescribed to over
90% of transplant recipients due to its proven efficacy and tolerability. However, tacrolimus is associated with a
distinctive triad of kidney-centered adverse effects: hypertension, hyperkalemia, and metabolic acidosis.
Intriguingly, this triad resembles the rare Mendelian disorder Familial Hyperkalemia and Hypertension (FHHt),
which results from over-activation of the NaCl-cotransporter (NCC) in the distal convoluted tubule. NCC activity
is regulated by the WNK/SPAK (With-no-lysine and Ste20/ SPS-1 -related- proline- alanine- rich protein kinase)
signaling pathway. In the distal convoluted tubule, kidney-specific WNK1 (KS-WNK1) is essential for activation
of the WNK/SPAK/NCC cascade. Mice carrying human gain-of-function mutations in KS-WNK1 have over-
activation of this pathway, thereby mimicking both the CNI- and FHHt-associated phenotypes. We propose that
KS-WNK1 acts as a scaffold, recruiting WNK/SPAK components into biomolecular condensates known as WNK
bodies, thereby amplifying NCC signaling. Biomolecular condensates are membraneless compartments that
concentrate macromolecules through phase separation, creating localized environments that regulate specific
biochemical reactions. The study of condensate biology has reshaped our understanding of intracellular
organization and has sparked growing interest in pharmacologic strategies to target these structures. Our
preliminary data indicate that tacrolimus increases the abundance of WNK bodies, suggesting a direct
mechanistic link between CNIs, condensates, and NCC overactivation. The goal of this R01 is to use CNIs as
both an experimental tool and clinical model to manipulate WNK body composition, dynamics, and function,
while concurrently testing how CNIs alter kidney physiology th

## Key facts

- **NIH application ID:** 11365740
- **Project number:** 1R01DK142678-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Cary Ragan Boyd-Shiwarski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DK
- **Fiscal year:** 2026
- **Award amount:** $769,882
- **Award type:** 1
- **Project period:** 2026-04-16T00:00:00 → 2031-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11365740

## Citation

> US National Institutes of Health, RePORTER application 11365740, The molecular and physiologic effects of calcineurin inhibitors on WNK body bimolecular condensates (1R01DK142678-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11365740. Licensed CC0.

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