2-Deoxy-D-glucose ameliorates PKD progression

Marco Chiaravalli, Isaline Severine Marie-Josephe Rowe, Valeria Mannella, Giacomo Quilici, Tamara Canu, Veronica Bianchi, Antonia Gurgone, Sofia Antunes, Patrizia D'Adamo, Antonio Esposito, Giovanna Musco, Alessandra Boletta

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-D-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of 13C-glucose and conversion to 13C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP- Activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in bothmodel systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.

Original languageEnglish
Pages (from-to)1958-1969
Number of pages12
JournalJournal of the American Society of Nephrology
Volume27
Issue number7
DOIs
Publication statusPublished - 2016

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Deoxyglucose
Autosomal Dominant Polycystic Kidney
Cystic Kidney Diseases
Glucose
Gene Silencing
Disease Progression
Acetyl-CoA Carboxylase
AMP-Activated Protein Kinases
Glycolysis
Chronic Kidney Failure
Lactic Acid
Histology
Therapeutics
Kidney
Brain

ASJC Scopus subject areas

  • Nephrology

Cite this

2-Deoxy-D-glucose ameliorates PKD progression. / Chiaravalli, Marco; Rowe, Isaline Severine Marie-Josephe; Mannella, Valeria; Quilici, Giacomo; Canu, Tamara; Bianchi, Veronica; Gurgone, Antonia; Antunes, Sofia; D'Adamo, Patrizia; Esposito, Antonio; Musco, Giovanna; Boletta, Alessandra.

In: Journal of the American Society of Nephrology, Vol. 27, No. 7, 2016, p. 1958-1969.

Research output: Contribution to journalArticle

Chiaravalli, M, Rowe, ISM-J, Mannella, V, Quilici, G, Canu, T, Bianchi, V, Gurgone, A, Antunes, S, D'Adamo, P, Esposito, A, Musco, G & Boletta, A 2016, '2-Deoxy-D-glucose ameliorates PKD progression', Journal of the American Society of Nephrology, vol. 27, no. 7, pp. 1958-1969. https://doi.org/10.1681/ASN.2015030231
Chiaravalli, Marco ; Rowe, Isaline Severine Marie-Josephe ; Mannella, Valeria ; Quilici, Giacomo ; Canu, Tamara ; Bianchi, Veronica ; Gurgone, Antonia ; Antunes, Sofia ; D'Adamo, Patrizia ; Esposito, Antonio ; Musco, Giovanna ; Boletta, Alessandra. / 2-Deoxy-D-glucose ameliorates PKD progression. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 7. pp. 1958-1969.
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