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Abstract: FR-PO616

A New Mouse Model for Dent Disease 1 with Impaired Mitochondrial Metabolism Develops CKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic


  • de Combiens, Elise, Sorbonne Universite, Paris, Île-de-France, France
  • Frachon, Nadia, Sorbonne Universite, Paris, Île-de-France, France
  • Sakhi, Imene Bouchra, Universitat Zurich, Zurich, Zurich, Switzerland
  • Lourdel, Stéphane, Sorbonne Universite, Paris, Île-de-France, France

Group or Team Name

  • Renal Physiology and Tubulopathies.

Dent disease 1 is a rare tubular disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, and progressive renal failure. It is caused by inactivating mutations of the CLCN5 gene encoding for the 2Cl-/H+ exchanger ClC-5. In the kidney, ClC-5 is mainly expressed in early endosomes of proximal tubules (PT) cells where it is thought to optimize the function of the vacuolar H+-ATPase to ensure the proper endocytosis of LMW proteins. To better understand the cellular mechanisms involved in Dent disease, we have generated a Knock-In (KI) mouse model carrying a patient mutation of ClC-5. Preliminary data from the lab show altered PT endo-lysosomal function and consequent impaired autophagy. Whether this altered pathway could impact mitochondrial metabolism was previously unknown. Therefore, we used this novel mouse model to evaluate the contributing factors of the progressive metabolic disorder observed in Dent disease.


The renal phenotype of WT and KI ageing mice was explored using metabolic cages. Their mitochondrial distribution and function were assessed with immunofluorescence, western blot, transmission electronic microscopy, and targeted urinary metabolomic analysis.


10-month-old KI showed an impaired general renal function accompanied by increased fractional excretions of calcium, phosphate, magnesium, indicating a PT dysfunction. KI mice expressed more Lipocalin 2, a tissue damage marker, in their kidneys and showed its increased excretion. These changes were associated with renal fibrosis and inflammation. The renal expression of PGC1 alpha, a marker of mitochondrial biogenesis, was increased between 4 to 10 months in KI mice. It was associated to an increased mitochondrial mass at 10 months. The shape of PT mitochondria from KI mice was altered even at young stages. Additionally, the loss of metabolites crucial for mitochondrial metabolism (alpha ketoglutarate, oxaloacetic acid, etc.) was highlighted in KI mice.


In conclusion, our mouse model suggests that altered endocytosis, consequent to ClC-5 mutation, impairs autophagy and leads to the accumulation of defective mitochondria. This would therefore potentiate renal damages of various origins with age, and a subsequent renal failure. This study opens up new perspectives for the development of therapeutic strategies.


  • Government Support – Non-U.S.