Abstract: TH-PO0008
Inducible Renal Slc26a6-Mediated Oxalate Secretion Defends Against Hyperoxalemia Under Conditions of Increased Oxalate Loading
Session Information
- Mineral Balance: Physiology and Pathophysiology
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Thomson, Robert Brent, Yale School of Medicine, New Haven, Connecticut, United States
- Zimmermann, Amelie Audrey, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany
- Jiang, Zhirong, Yale School of Medicine, New Haven, Connecticut, United States
- Knauf, Felix, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Aronson, Peter S., Yale School of Medicine, New Haven, Connecticut, United States
Background
Impaired oxalate homeostasis is associated with kidney and cardiovascular diseases and systemic inflammation. The anion exchanger Slc26a6 plays a crucial role in regulating oxalate homeostasis by mediating apical membrane oxalate secretion in the intestine and proximal tubule of the kidney. However, the relative contributions of intestinal and renal Scl26a6 to oxalate homeostasis are not known.
Methods
Founder mice with LoxP sites flanking exons 2-4 of Slc26a6 were generated using CRISPR-Cas9 technology. These were crossed with ß-actin-, villin-, or Pax8-cre mice to generate mice with global, intestine-, or kidney-specific deletion of Slc26a6. Successful Slc26a6 gene deletion was verified by qPCR. Plasma and urine oxalate was measured enzymatically. Chloride-dependent oxalate uptake in isolated renal membrane vesicles was assayed to determine chloride-oxalate exchange activity. Renal brush border Slc26a6 expression was assessed by Western blotting.
Results
Successful deletion of Slc26a6 was confirmed in mice with global and tissue-specific Slc26a6 deletion. Global deletion of Slc26a6 resulted in a 230% increase in urine oxalate excretion and a 413% increase in plasma oxalate, confirming previous findings of hyperoxaluria and hyperoxalemia due to increased net absorption of dietary oxalate in global Slc26a6 null mice. In contrast, intestine-specific deletion of Slc26a6 caused a similar 161% increment in oxalate excretion but no increase in plasma oxalate because of a 156% increase in fractional excretion of oxalate (FEOX). This increase in renal tubular oxalate secretion correlated with a 45% increase in renal brush border Slc26a6 expression associated with an 86% increase in chloride-oxalate exchange activity. In mice challenged with a high oxalate diet, kidney-specific deletion of Slc26a6 resulted in a 140% increment in plasma oxalate due to a 57% decrease in FEOX.
Conclusion
These findings uncover a novel defense mechanism in which inducible renal Slc26a6-dependent oxalate secretion buffers plasma oxalate levels under conditions of an increased oxalate load resulting either from intestine-specific deletion of Slc26a6 or from ingestion of a high oxalate diet.
Funding
- NIDDK Support