التفاصيل البيبلوغرافية
| العنوان: |
The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI. |
| المؤلفون: |
Trepiccione, Francesco, Iervolino, Anna, D'Acierno, Mariavittoria, Siccardi, Sabrina, Costanzo, Vincenzo, Sardella, Donato, De La Motte, Luigi R., D'Apolito, Luciano, Miele, Antonio, Perna, Alessandra F., Capolongo, Giovanna, Zacchia, Miriam, Frische, Sebastian, Nielsen, Rikke, Staiano, Leopoldo, Sambri, Irene, De Cegli, Rossella, Unwin, Robert, Eladari, Dominique, Capasso, Giovambattista |
| المصدر: |
Science Translational Medicine; 11/1/2023, Vol. 15 Issue 720, p1-12, 12p |
| مصطلحات موضوعية: |
DAPAGLIFLOZIN, GLYCOGEN storage disease type II, GLYCOGEN storage disease, SODIUM-glucose cotransporter 2 inhibitors, PROXIMAL kidney tubules, KIDNEY physiology, KIDNEY tubules |
| مستخلص: |
Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS. Editor's summary: Glycogen storage disease XI is caused by loss-of-function mutations in the glucose transporter GLUT2 that result in glycogen accumulation in external organs. Focusing on the renal complications of this disease, Trepiccione et al. show that restricting glucose entry into the proximal tubule using the SGLT2 inhibitor dapagliflozin improved renal tubule glycogen accumulation and dysfunction in mice with kidney-specific GLUT2 knockout. Treatment of a single adult patient with dapagliflozin reduced glycogen content in shed urinary cells and improved serum potassium and phosphate concentrations, showing proof-of-concept treatment for this form of glycogen storage disorder that awaits further clinical validation. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
