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Kidney Week

Abstract: SA-PO652

Evaluation of the Impact of SGLT2 Inhibitor Treatment in a Mouse Model of Dent Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • de Combiens, Elise, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Frachon, Nadia, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Lourdel, Stéphane, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
Background

Dent's disease is a rare disorder affecting the proximal tubule. It is characterized by urinary loss of low-molecular-weight proteins (LMWPs), and other electrolytes such as calcium. It generally progresses to chronic kidney disease (CKD), and is due to a mutation in the CLCN5 gene encoding the ClC-5 protein which plays a crucial role LMWPs endocytosis.
To study the mechanisms involved in the progression of this disease to CKD, we created a Knock In (KI) mouse model carrying a CLCN5 mutation. The transgenic mice develop the main clinical features observed in patients, presents fibrosis and inflammation with age, as well as an alteration of their glomerular filtration rate.
In an attempt to slow-down the progression of the disease to CKD, we treated our mice with empagliflozin, a SGLT2 inhibitor which have been described to display nephroprotective effects in many diabetic and non-diabetic CKD patients.

Methods

empagliflozin was administered in the diet of mice for 8 months at a dose of 30mg/kg of mice per day. At 10 months, mouse kidneys were collected to evaluate fibrosis and inflammation and quantify the tubular damage marker NGAL.

Results

Surprisingly, the treatment did not slow-down the progression of Dent's disease, as the mice showed significant inflammation and fibrosis at 10 months, as well as high levels of NGAL compared with WT mice.

Conclusion

Contrary to other murine models of CKD, empagliflozin does not appear to slow-down the progression of Dent's disease. Some clinical studies suggest that SGLT2 inhibitors act synergistically with inhibitors of the renin angiotensin system, another treatment commonly administered in patient with CKD. It would therefore be interesting to evaluate the effect of these 2 treatments on our mouse model.

Funding

  • Government Support – Non-U.S.