Kidney Week

Abstract: SA-PO0472

Kir5.1-Modulated Potassium Flux Stimulates an Anabolic Kidney Phenotype

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Inoue, Masaki, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Masaki Inoue, MD, PhD

• Terker, Andrew S., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Andrew S. Terker, MD, PhD, FASN

• Delpire, Eric J., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Eric J. Delpire, PhD

• Wu, Aihua, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Aihua Wu, PhD

Group or Team Name

• Terker Lab.

Background

Maintaining potassium (K) homeostasis imposes a significant metabolic burden on the kidney, requiring constant energy to support electrolyte transport and prevent K imbalance. Reduced dietary K triggers nephron remodeling and enhanced proximal tubule sodium (Na) reabsorption—adaptations requiring metabolic reprogramming. The proximal tubule inwardly rectifying K channel Kir4.2 and its partner Kir5.1 mediate this response but the metabolic pathways supporting these processes are poorly understood

Methods

We generated a mouse expressing a dominant-negative Kir5.1 channel (Kir5.1C496del) and studied it under normal and K-free diets. Thallium flux assays confirmed dominant-negative function. Blood and urine electrolytes were measured by ion-specific electrodes. Protein and metabolite levels were quantified using Western blot and GC-MS, respectively. Deuterium-labeled water with GC-MS assessed de novo palmitate synthesis. Kidney proteomics was performed after 4 days of 0 per cent vs. 1 per cent K diet. Glycolytic flux was measured in ex vivo cortical kidney punches using Seahorse analysis. Immunofluorescence was performed to measure Ki67.

Results

Kir5.1^DN mice displayed a K-wasting phenotype, worsened by K restriction, with reduced Na transporter expression and metabolic acidosis. Low K diet increased kidney size and epithelial proliferation in Kir5.1^WT mice—responses blunted in Kir5.1^DN animals.
Proteomics identified 559 differentially expressed proteins, including upregulation of carbohydrate, glutamine, and fatty acid metabolism pathways. Pyruvate kinase was most upregulated. Low K increased glycolytic flux and metabolites (PEP, G3P) in Kir5.1^WT but not Kir5.1^DN mice. Glycolytic enzyme expression and amino acid levels were similarly reduced in Kir5.1^DN animals. De novo lipogenesis was also impaired, with reduced palmitate synthesis in mutant mice.

Conclusion

Results uncover metabolic details of a low K-stimulated anabolic kidney program, including stimulation of glycolytic and de novo lipogenic pathways. These changes require intact Kir5.1 channel function and highlight a therapeutic role for targeting Kir channels to modulate cell physiology and metabolism.

Funding

• Other NIH Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20254pa8he7j