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Abstract: PO1311

Treatment with 4-Phenylbutyrate Reduces Low-Molecular-Weight Proteinuria in a Clcn5 Knock-In Mouse Model for Dent Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Perdomo-Ramirez, Ana, Hospital Universitario Nuestra Senora de la Candelaria, Santa Cruz de Tenerife, Canarias, Spain
  • Ramos-Trujillo, Elena, Universidad de La Laguna, La Laguna, Islas Canarias, Spain
  • Mura Escorche, Glorian, Universidad de La Laguna, La Laguna, Islas Canarias, Spain
  • Garcia-Nieto, Victor, Hospital Universitario Nuestra Senora de la Candelaria, Santa Cruz de Tenerife, Canarias, Spain
  • Machado, Jose-David, Universidad de La Laguna, La Laguna, Islas Canarias, Spain
  • Claverie-Martin, Felix, Hospital Universitario Nuestra Senora de la Candelaria, Santa Cruz de Tenerife, Canarias, Spain
Background

Dent disease-1 (DD1) is a rare X-linked tubular disorder characterized by low-molecular-weight-proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene, which encodes the voltage-gated ClC-5 chloride/proton antiporter. ClC-5 is expressed predominantly in the kidney and participates in the acidification of proximal tubule endosomes. Currently, the treatment of DD1 is only supportive and focused in delaying disease progression. Our group has generated a Clcn5 knock-in (KI) mouse that presents the main clinical manifestations of DD1 and carries the pathogenic mutation p.V523del, which causes partial ClC-5 retention in the endoplasmic reticulum. Here, we aimed to assess the ability of sodium 4-phenylbutyrate (4-PBA), a small chemical chaperone, to ameliorate DD1 symptoms in this mouse model.

Methods

Twelve-weeks old male Clcn5 KI mice (n=50) and WT (n=33) littermates were divided into 2 groups, one was treated with 250 mg/kg/day of 4-PBA in drinking water, for 31 days, whereas the other group was given water without the drug for the same amount of time. Mice were placed in metabolic cages before and after treatment for 24h. Urinary β2-microglobulin and serum and urinary creatinine were measured by ELISA. Calcium and phosphate concentrations in urine were estimated using colorimetric kits. Water and food intake and 24-h urinary excretion were also measured, and mice body weights were monitored.

Results

We observed a significant reduction of β2-microglobulin urinary excretion in KI mice treated with 4-PBA compared to non-treated animals (p=0.0004). Glomerular filtration rate was also improved in treated mice (p=0.03). Urine production, urinary calcium and phosphate levels did not show differences compared with non-treated mice.

Conclusion

4-PBA reduces LMWP in Clcn5 KI mice, suggesting that this treatment could represent a promising therapeutic option for some DD1 patients.

Funding

  • Government Support – Non-U.S.