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Abstract: TH-OR010

Investigation of the Renal Phenotype of a Novel Mouse Model with Dent Disease

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Sakhi, Imène B., INSERM U1138 Centre de recherche des Cordeliers, Paris, France
  • Bignon, Yohan, INSERM U1138 Centre de recherche des Cordeliers, Paris, France
  • Frachon, Nadia, INSERM U1138 Centre de recherche des Cordeliers, Paris, France
  • Picard, Nicolas, LBTI CNRS U5305 Institut de Biologie et Chimie des Protéines, Paris, Paris, France
  • Lourdel, Stéphane, INSERM U1138 Centre de recherche des Cordeliers, Paris, France

Group or Team Name

  • Renal physiology and tubulopathies
Background

Dent disease is a rare hereditary renal proximal disorder that predominantly affects young males. The disease is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, kidney stones and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl-/H+ exchanger ClC-5 have been identified in more than 60 % of patients with Dent disease. ClC-5 is essentially expressed in early endosomes of proximal tubules (PT) where it optimizes the function of the V-type H+ ATPase to ensure an efficient endocytosis of LMW proteins, and therefore to avoid their loss into the urine.
The functional consequences of CLCN5 mutations have previously been investigated in heterologous expression systems. It has been shown that 60 % of the mutations lead to a defect in protein folding and processing, such as the previously published N340K pathogenic ClC-5 mutation. As a consequence, the misfolded ClC-5 are retained within the endoplasmic reticulum (ER). Here, we have investigated the consequences of the N340K mutation using a transgenic mouse model.

Methods

Daily food, water intake, body weight and urine excretion data were collected in metabolic cages for N340K and WT mice. Urine as well as blood samples were analysed for ions, proteins, glucose and creatinine to detect kidney dysfunction as observed in patients with Dent disease. Expression and localization of proteins involved in receptor-mediated endocytosis of LMW proteins were studied by Western blot and on kidney sections by immunofluorescence in WT and N340K male mice.

Results

The N340K mice showed an increased urinary calcium and glucose excretion, a decreased urinary pH, and a severe LMW proteinuria, recapitulating common features of Dent disease. Megalin, a multi-ligands receptor involved in the endocytosis of LMW proteins was less expressed at the apical border of N340K mouse PTs.

Conclusion

The present study validates a new Dent disease mouse model carrying a pathogenic mutation of ClC-5. It will help to better understand the molecular basis of Dent disease, such as the link between an altered ClC-5 and defective proximal tubule endocytosis. In the long term, our mouse model could be used to assess therapeutic approaches for the rescue of a proper proximal tubule cell function.

Funding

  • Government Support - Non-U.S.