Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

D’Acierno, Mariavittoria; Resaz, Roberta; Iervolino, Anna; Nielsen, Rikke; Sardella, Donato; Siccardi, Sabrina; Costanzo, Vincenzo; D’Apolito, Luciano; Suzumoto, Yoko; Segalerba, Daniela; Astigiano, Simonetta; Perna, Alessandra F.; Capasso, Giovambattista; Eva, Alessandra; Trepiccione, Francesco

doi:10.1681/asn.2021070935

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…Dapagliflozin minimized further glucose influx and not only prevented cortical glycogen accumulation but also increased the membrane expression of SGLT2 as an indication of improved PT cell function. We have demonstrated a similar process in the glycogen storage disease Ib ( 12 , 13 ).…”

Section: Discussionsupporting

confidence: 60%

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI

Trepiccione,

Iervolino,

D’Acierno

et al. 2023

Sci. Transl. Med.

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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. GLUT2 Pax8Cre+ 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.

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Section: Discussionsupporting

confidence: 60%

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI

Trepiccione,

Iervolino,

D’Acierno

et al. 2023

Sci. Transl. Med.

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“…As such, variable stages of kidney disease, from proximal and distal tubulopathies to irreversible glomerular injury, may affect the outcome of these patients [115]. In a mouse model of GSD1b that accumulated glycogen in the kidney, Trepiccione and collaborators [116] showed that the main protein markers of proximal tubule function were all down-regulated. These markers included the major sodium and phosphate transporters along the proximal tubule (NHE 3 and NaPi2A), the two main renal glucose transporters located on the apical and the basolateral membranes of the proximal tubular cells (SGLT2 and GLUT2) and AQP1, the principal aquaporin water-transporting protein in the plasma membranes of the proximal tubular cells.…”

Section: Could Sglt2 Inhibitors Help Gsd1b Patients Beyond Treating T...mentioning

confidence: 99%

Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors

et al. 2023

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Glycogen storage disease type Ib (GSD1b) is due to a defect in the glucose-6-phosphate transporter (G6PT) of the endoplasmic reticulum, which is encoded by the SLC37A4 gene. This transporter allows the glucose-6-phosphate that is made in the cytosol to cross the endoplasmic reticulum (ER) membrane and be hydrolyzed by glucose-6-phosphatase (G6PC1), a membrane enzyme whose catalytic site faces the lumen of the ER. Logically, G6PT deficiency causes the same metabolic symptoms (hepatorenal glycogenosis, lactic acidosis, hypoglycemia) as deficiency in G6PC1 (GSD1a). Unlike GSD1a, GSD1b is accompanied by low neutrophil counts and impaired neutrophil function, which is also observed, independently of any metabolic problem, in G6PC3 deficiency. Neutrophil dysfunction is, in both diseases, due to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), a potent inhibitor of hexokinases, which is slowly formed in the cells from 1,5-anhydroglucitol (1,5-AG), a glucose analog that is normally present in blood. Healthy neutrophils prevent the accumulation of 1,5-AG6P due to its hydrolysis by G6PC3 following transport into the ER by G6PT. An understanding of this mechanism has led to a treatment aimed at lowering the concentration of 1,5-AG in blood by treating patients with inhibitors of SGLT2, which inhibits renal glucose reabsorption. The enhanced urinary excretion of glucose inhibits the 1,5-AG transporter, SGLT5, causing a substantial decrease in the concentration of this polyol in blood, an increase in neutrophil counts and function and a remarkable improvement in neutropenia-associated clinical signs and symptoms.

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“…Indeed, empagliflozin reduces NHE3 transport activity in rats, showing a tight relation between SGLT2 and NHE3 transporters [ 46 ]. This has been recently highlighted in a mice model mimicking the Fanconi syndrome secondary to glycogen storage disease 1b [ 47 ].…”

Section: The Roles Of Nhe3 In the Control Of Blood Pressurementioning

confidence: 99%

Kidney and blood pressure regulation—latest evidence for molecular mechanisms

Suzumoto

Zucaro

Iervolino

et al. 2023

Clinical Kidney Journal

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Hypertension is one of the major health problems leading to the development of cardiovascular diseases. Despite a rapid expansion in global hypertension prevalence, molecular mechanisms leading to hypertension are not fully understood largely due to the complexity of pathogenesis involving several factors. Salt intake is recognized as a leading determinant of blood pressure, since reduced dietary salt intake is related to lower morbidity and mortality, and hypertension in relation with cardiovascular events. Compared with salt-resistant populations, salt-sensitive individuals exhibit high sensitivity in blood pressure responses according to changes in salt intake. In this setting, kidney plays a major role on the maintenance of blood pressure under the hormonal control of Renin-Angiotensin-Aldosterone System (RAAS). In the present review, we summarize the current overview on the molecular mechanisms for modulation of blood pressure associated with renal ion channels/transporters including NHE3, NKCC2, NCC, ENaC and Pendrin expressed in different nephron segments. In particular, recent studies on experimental animal models with deletion of renal ion channels led to the identification of several crucial physiological mechanisms and molecules involved in hypertension. These findings could further provide a potential for novel therapeutic approaches applicable on human patients with hypertension.

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Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

Cited by 8 publications

References 34 publications

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI

Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors

Kidney and blood pressure regulation—latest evidence for molecular mechanisms

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