Partial Klotho Deletion in the Renal Distal Segment Does Not Affect Ca2+ Handling
- 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
- Grigore, Teodora, Radboudumc, Nijmegen, Gelderland, Netherlands
- Zuidscherwoude, Malou, Radboudumc, Nijmegen, Gelderland, Netherlands
- Bos, Caro, Radboudumc, Nijmegen, Gelderland, Netherlands
- Olauson, Hannes, Radboudumc, Nijmegen, Gelderland, Netherlands
- Hoenderop, Joost, Radboudumc, Nijmegen, Gelderland, Netherlands
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 (PO43-) 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).
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.
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.
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.