TY - JOUR
T1 - Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b
AU - D'Acierno, Mariavittoria
AU - Resaz, Roberta
AU - Iervolino, Anna
AU - Nielsen, Rikke
AU - Sardella, Donato
AU - Siccardi, Sabrina
AU - Costanzo, Vincenzo
AU - D'Apolito, Luciano
AU - Suzumoto, Yoko
AU - Segalerba, Daniela
AU - Astigiano, Simonetta
AU - Perna, Alessandra F
AU - Capasso, Giovambattista
AU - Eva, Alessandra
AU - Trepiccione, Francesco
PY - 2022/10
Y1 - 2022/10
N2 - Background: Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires kidney replacement therapy. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype. Methods: We utilized an inducible mouse model of GSD1b, TM-G6PT
-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and, thus, to prevent glycogen accumulation, we administered a SGLT2-inhibitor, dapagliflozin, to TM-G6PT
-/- mice. Results: In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis towards lysis and restored expression levels of the main proximal tubule functional markers. Conclusion: We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat GSD1b patients.
AB - Background: Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires kidney replacement therapy. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype. Methods: We utilized an inducible mouse model of GSD1b, TM-G6PT
-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and, thus, to prevent glycogen accumulation, we administered a SGLT2-inhibitor, dapagliflozin, to TM-G6PT
-/- mice. Results: In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis towards lysis and restored expression levels of the main proximal tubule functional markers. Conclusion: We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat GSD1b patients.
KW - Animals
KW - Disease Models, Animal
KW - Glucose/metabolism
KW - Glycogen Storage Disease Type I/complications
KW - Glycogen/metabolism
KW - Kidney Tubules, Proximal/metabolism
KW - Kidney/metabolism
KW - Mice
KW - Sodium-Glucose Transporter 2/metabolism
U2 - 10.1681/ASN.2021070935
DO - 10.1681/ASN.2021070935
M3 - Journal article
C2 - 35820785
SN - 1046-6673
VL - 33
SP - 1864
EP - 1875
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 10
ER -