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Abstract: TH-PO555

Regulation of Claudins by Metabolic Acidosis via Calcium-Sensing Receptor in Rat Kidney

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Kim, Gheun-Ho, Hanyang University College of Medicine, Seoul, Korea (the Republic of)
  • Jo, Chor ho, Hanyang University, Seoul, Korea (the Republic of)
  • Kim, Sua, Hanyang University, Seoul, Korea (the Republic of)
Background

Metabolic acidosis (MA) may present with nephrocalcinosis and nephrolithiasis because of hypercalciuria. Most of the calcium reabsorption paracelluarly occurs through tight junctions in the proximal tubule (PT) and thick ascending limb (TAL) whereas the distal convoluted tubule and connecting tubule are the major regulatory sites of active calcium transport. However, the regulatory contribution of paracelluar calcium transport in the PT and TAL to hypercalciuria in MA remains to be elucidated.

Methods

Male Sprague-Dawley rats were randomly divided into four groups to see the effects of calcium-sensing receptor (CaSR) stimulation (using cinacalcet) and inhibition (using NPS-2143) in the presence of MA: controls (n=6), cinacalcet-treated (n=6), NH4Cl-loaded (n=6), and NH4Cl/NPS-2143-cotreated rats (n=6). After seven days’ animal experiment, renal claudin expressions were examined by semiquantitative immunoblotting, qPCR analysis, and immunofluorescence microscopy.

Results

Urinary calcium excretion was insignificantly increased by cinacalcet treatment, and it is significantly elevated by NH4Cl loading and reversed by NPS-2143 coadministration. Renal claudin-2 protein/mRNA were not altered by cinacalcet treatment, and they were suppressed by NH4Cl loading and recovered by NPS-2143 coadministration. Claudin-16 protein/mRNA and claudin-19 protein/mRNA were not altered by cinacalcet treatment, and they were also downregulated by NH4Cl loading and reversed by NPS-2143 coadministration. Consistently, claudin-14 protein/mRNA were upregulated by NH4Cl loading and reversed reversed by NPS-2143 coadministration. Furthermore, CaSR protein/mRNA were upregulated by NH4Cl loading and reversed by NPS-2143 coadministration. The effects of acid loading were confirmed by immunofluorescence microscopy.

Conclusion

In metabolic acidosis, not only claudin-2 in PT but also claudin-16/19 in TAL are downregulated to produce hypercalciuria. The CaSR in rat kidney appears to have a regulatory role in MA-induced hypercalciuria.

Funding

  • Commercial Support