Kidney Week

Abstract: SA-PO304

Is Claudin 16 Required for the Effect of Parathyroid Hormone (PTH) and Calcium Sensing-Receptor (CaSR) on Calcium and Magnesium Reabsorption in the Cortical Thick Ascending Limb?

Session Information

• Fluid and Electrolytes: Basic - II
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Prot-Bertoye, Caroline, INSERM, UMRS1138- CNRS- ERL8228, Paris, France

Caroline Prot-Bertoye,

• Figueres, Lucile, INSERM, UMRS1138- CNRS- ERL8228, Paris, France

Lucile Figueres,

• Ferriere, Elsa, INSERM, UMRS1138- CNRS- ERL8228, Paris, France

Elsa Ferriere,

• Brideau, Gaëlle, INSERM, UMRS1138- CNRS- ERL8228, Paris, France

Gaëlle Brideau,

• Griveau, Camille, INSERM, UMRS1138- CNRS- ERL8228, Paris, France

Camille Griveau,

• Chaussain, Catherine, EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School, Paris Descartes University, Paris, France

Catherine Chaussain,

• Bardet, Claire, EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School, Paris Descartes University, Paris, France

Claire Bardet,

• Breiderhoff, Tilman, Department of Pediatric Nephrology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Tilman Breiderhoff,

• Müller, Dominik, Department of Pediatric Nephrology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Dominik Müller,

• Houillier, Pascal, INSERM, UMRS1138- CNRS- ERL8228, Paris, France

Pascal Houillier,

Background

The cortical thick ascending limb of the loop of Henle (CTAL) reabsorbs 25% of the filtered calcium (Ca) and 70% of the filtered magnesium (Mg), along the paracellular pathway. The expression of claudin 16 (Cldn16) at the tight junction is required for a normal paracellular permeability and selectivity to Ca and Mg. Loss-of-function mutations of Cldn16 in the CTAL cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). No specific treatment has been developed so far.
PTH increases Ca and Mg transport and CaSR decreases Ca transport across the CTAL but the mechanisms involved are imprecise. Recent studies suggested that both PTH and CaSR agonists act on Cldn14, which may control Cldn16 function and/or expression and, eventually, paracellular reabsorption of Ca and Mg. Our objective was to assess whether Cldn16 is actually involved in the effect of PTH and CaSR on Ca and Mg reabsorption in CTAL.

Methods

CTAL dissected from Cldn16^+/+ and Cldn16^-/- male mice were microperfused in vitro to measure transepithelial ions absorption under symmetrical conditions. Measurements were made under control condition and after addition of PTH (10^-10 M) or of the CaSR antagonist NPS2143 (10^-6 M).

Results

PTH and NPS2143 increased Ca reabsorption in Cldn16^+/+ CTAL (+44 %, n= 5, p=0.06; and +23 %, n= 7, p=0.047, respectively) and Cldn16^-/- CTAL (+37 %, n=8, p=0.02; and +59 %, n=7, p=0.02, respectively).
PTH increased Mg reabsorption in Cldn16^+/+ CTAL (+57 %, n=7, p=0.03) and in Cldn16^-/- CTAL (+27%, n=5, p=0.06). The effect of NPS2143 on Mg reabsorption is currently under study.

Conclusion

Cldn16 is not necessary for the effect of PTH and CaSR on Ca reabsorption by native CTAL. Cldn16 is not necessary for the effect of PTH on Mg reabsorption by native CTAL. Our results suggest that the current model describing the effect of PTH and CaSR on Cldn16 might not be accurate. Our results constitute a proof of concept to develop new therapeutic strategies based on CaSR inhibitor and/or PTH receptor agonist for FHHNC.

Funding

• Government Support - Non-U.S.