Kidney Week

Abstract: FR-PO292

Partial Klotho Deletion in the Renal Distal Segment Does Not Affect Ca2+ Handling

Session Information

• Bone and Mineral Metabolism: Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Grigore, Teodora, Radboudumc, Nijmegen, Gelderland, Netherlands

Teodora Grigore,

• Zuidscherwoude, Malou, Radboudumc, Nijmegen, Gelderland, Netherlands

Malou Zuidscherwoude,

• Bos, Caro, Radboudumc, Nijmegen, Gelderland, Netherlands

Caro Bos,

• Olauson, Hannes, Radboudumc, Nijmegen, Gelderland, Netherlands

Hannes Olauson,

• Hoenderop, Joost, Radboudumc, Nijmegen, Gelderland, Netherlands

Joost Hoenderop,

Background

Klotho is a protein important in health and disease, as decrease of circulating Klotho levels is correlated with age increase and chronic kidney disease (CKD) progression. This highlights Klotho as a potential early biomarker for CKD, as well as a potential therapeutic strategy to improve health and lifespan of patients. Klotho influences renal electrolyte handling by modulating renal reabsorption of phosphate (PO₄^3-) and calcium (Ca²⁺) through Ca²⁺ channel TRPV5 and Na⁺/Pi co-transporter NPT2a, and by interacting with renal phosphaturic hormone fibroblast growth factor-23 (FGF23).

Methods

The mouse model with a partial deletion of Klotho (Ksp-KL^-/-) in the distal convoluted tubule (DCT) was generated using the Cre-Lox recombination system, and was characterized with a disrupted mineral metabolism, with hyperphosphatemia, elevated FGF23 levels and decreased parathyroid hormone levels.
An interventional study was performed on Ksp-KL^-/- mice by subjecting the mice to a 0.02% Ca²⁺ diet for 3 weeks immediately after weaning. 24-hour urine and blood samples were collected using metabolic cages, and kidney and intestines were processed and relevant gene expression levels were analysed (qPCR). This study aimed to assess Ca²⁺ handling in Ca²⁺-deficient Ksp-KL^-/- mice to increase our understanding of electrolyte disturbance.

Results

Urinary, serum and fecal Ca²⁺ levels were not influenced by the Ca²⁺ deficient diet or the genotype of the animals. Renal expression of Klotho, Trpv5 and Npt2a was not significantly changed in Ksp-KL^-/- mice compared to Ksp-KL^+/+ mice. Intestinal expression of Trpv6 and Npt2b did not indicate a compensation towards intestinal electrolyte handling.

Conclusion

Partial deletion of Klotho (21%) in the DCT does not affect renal or intestinal Ca²⁺ handling, contrary to the global deletion of Klotho. We speculate that this may be due to insufficient challenge on the Ca²⁺ metabolism of the mice, as well as residual Klotho amounts that are sufficient to maintain normocalcemia and normocalciuria.