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Kidney Week

Abstract: TH-PO727

Renal Ablation of GLUT2 Leads to Intracellular Glycogen Accumulation and Recapitulates the Fanconi Bickel Syndrome

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Iervolino, Anna, Biogem, Ariano Irpino, Italy
  • De la motte, Luigi Regenburgh, University of Campania Luigi Vanvitelli, Napoli, Italy
  • Petrillo, Federica, Biogem, Ariano Irpino, Italy
  • Prosperi, Federica, Biogem, Ariano Irpino, Italy
  • Costanzo, Vincenzo, University of Bologna, Bologna, Italy
  • Capasso, Giovambattista, University of Campania Luigi Vanvitelli, Napoli, Italy
  • Trepiccione, Francesco, University of Campania Luigi Vanvitelli, Napoli, Italy
Background

Fanconi-Bickel syndrome, also known as glycogenosis type XI, is characterized by hepatic glycogen accumulation and proximal renal tubular dysfunction. Patients mainly suffer for a typical renal Fanconi syndrome associated with fasting hypoglycaemia. Currently, there is no causative therapy beside fluid and electrolyte supplementation. Loss of function mutations of SLC2A2, encoding for GLUT2, causes FBS. Impairment of GLUT2 alters glucose metabolism in hepatocytes and increases glycogen accumulation. Since the cells of the proximal tubules share a similar glucose metabolism as hepatocytes, a similar mechanism could be hypothesized, but no evidences so far has been provided

Methods

In order to generate an experimental model of FBS, we selectively knock-out GLUT2 expression in PAX8 expressing cells by mean of a Cre-Lox recombination strategy. This approach results in an efficient ablation of GLUT2 in the renal cortex

Results

GLUT2 cKO mice recapitulate the renal phenotype of FBS patients. They present with normo-glycaemic glycosuria and no signs of altered glucose metabolism when challenged with a glucose load. Glycosuria decreases, but is still detectable after fasting. GLUT2 cKO mice present an osmotic driven polyuria that improves by reducing theosmotic load. cKO mice present low molecular weight proteinuria and phosphaturia. This latter is sustained by a downregulation of Napi2a abundance in the cortex of GLUT2 cKO mice. When challenged with a sodium bicarbonate load, at serum level of bicarbonate equal as control mice, they excrete a double amount of bicarbonate, showing that GLUT2 ablation lead to proximal renal tubular acidosis. At histology, the proximal tubule cells appear hypertrophic compared with littermate controls. Quantification of renal cortical glycogen content shows a three fold increase abundance in cKO mice, suggesting that GLUT2 ablation alters significantly the intracellular glucose metabolism

Conclusion

We generate a mouse model cKO for GLUT2 recapitulating FBS. We show that GLUT2 is crucial for intracellular glucose metabolism in the proximal tubule cells since its ablation leads to a severe glycogen accumulation and loos of function. This model is suitable for testing novel pharmacologic approach to rescue FBS