Kidney Week

Abstract: SA-PO0488

Effects of Tissue-Specific Slc26a1 Deletion on Sulfate Homeostasis

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

• Zimmermann, Amelie Audrey, Yale School of Medicine, New Haven, Connecticut, United States

Amelie Audrey Zimmermann

• Jiang, Zhirong, Yale School of Medicine, New Haven, Connecticut, United States

Zhirong Jiang, MD, PhD

• Thomson, Robert Brent, Yale School of Medicine, New Haven, Connecticut, United States

Robert Brent Thomson, PhD

• Knauf, Felix, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Felix Knauf, MD

• Aronson, Peter S., Yale School of Medicine, New Haven, Connecticut, United States

Peter S. Aronson, MD, FASN

Background

Inorganic sulfate deficiency has been implicated in the pathogenesis of musculoskeletal, neurodevelopmental, and metabolic disorders. Slc26a1 is a sulfate transporter that is highly expressed in multiple mammalian tissues of which three have been proposed to play key roles in sulfate homeostasis: sulfate is reabsorbed in the renal proximal tubule, absorbed in the intestine, and taken up by the liver for sulfation reactions. The relative roles of Slc26a1 expressed in each of these tissues in sulfate homeostasis is not known.

Methods

CRISPR-Cas9 technology was used to generate founder mice with LoxP sites flanking critical 5’ exons of Slc26a1. Mice with global, liver-, intestine-, or kidney-specific disruption of Slc26a1 were created by crossing founder mice with β-actin-, albumin-, villin-, or Pax8-cre mice, respectively. Plasma and urine sulfate concentrations were determined by turbidimetric assay. Tissue expression levels of Slc26a1 and Na-sulfate cotransporter Slc13a1 were evaluated by qPCR.

Results

Mice with global- or kidney-specific Slc26a1 deletion had similar 2/3 reductions in plasma sulfate and 3-fold increases in fractional excretion of sulfate (FESO₄) relative to respective wild-type or flox/flox littermate controls. In contrast, no difference in either plasma sulfate or FESO₄ relative to respective flox/flox controls was observed in mice with liver- or intestine-specific deletion of Slc26a1. Sulfate excretion rate, reflected by urine sulfate/creatinine ratio, was unaffected in all four groups. No compensatory changes were detected in expression of Slc13a1 in kidney and intestine of mice with global Slc26a1 deletion, or of Slc26a1 in non-targeted organs of mice with tissue-specific Slc26a1 deletion.

Conclusion

The similarly severe hyposulfatemia with markedly elevated FESO₄ observed in mice with global and kidney-specific Slc26a1 deletion strongly suggests that the hyposulfatemia in mice with global Slc26a1 deletion is primarily due to a defect in renal sulfate reabsorption. This conclusion was supported by the lack of detectable effects of Slc26a1 deletion from the liver or intestine on sulfate homeostasis. We conclude that Slc26a1 regulates plasma sulfate levels primarily through its activity mediating sulfate reabsorption in the kidney.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025xyj8y4mn