Dataset Information

2-Deoxy-d-Glucose Ameliorates PKD Progression.

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 (13)C-glucose and conversion to (13)C-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 both model 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.

SUBMITTER: Chiaravalli M

PROVIDER: S-EPMC4926967 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, caused in the majority of the cases by a mutation in either the PKD1 or the PKD2 gene. ADPKD is characterised by a progressive increase in the number and size of cysts, together with fibrosis and distortion of the renal architecture, over the years. This is accompanied by alterations in a complex network of signalling pathways. However, the underlying molecular mechanisms are not well characterised. Previously, we defined the PKD Signature, a set of genes typically dysregulated in PKD across different disease models from a meta-analysis of expression profiles. Given the importance of transcription factors (TFs) in modulating disease, we focused in this paper on characterising TFs from the PKD Signature. Our results revealed that out of the 1515 genes in the PKD Signature, 92 were TFs with altered expression in PKD, and 32 of those were also implicated in tissue injury/repair mechanisms. Validating the dysregulation of these TFs by qPCR in independent PKD and injury models largely confirmed these findings. STAT3 and RUNX1 displayed the strongest activation in cystic kidneys, as demonstrated by chromatin immunoprecipitation (ChIP) followed by qPCR. Using immunohistochemistry, we showed a dramatic increase of expression after renal injury in mice and cystic renal tissue of mice and humans. Our results suggest a role for STAT3 and RUNX1 and their downstream targets in the aetiology of ADPKD and indicate that the meta-analysis approach is a viable strategy for new target discovery in PKD. KEY MESSAGES: We identified a list of transcription factors (TFs) commonly dysregulated in ADPKD. Out of the 92 TFs identified in the PKD Signature, 35% are also involved in injury/repair processes. STAT3 and RUNX1 are the most significantly dysregulated TFs after injury and during PKD progression. STAT3 and RUNX1 activity is increased in cystic compared to non-cystic mouse kidneys. Increased expression of STAT3 and RUNX1 is observed in the nuclei of renal epithelial cells, also in human ADPKD samples.

Dataset Information

2-Deoxy-d-Glucose Ameliorates PKD Progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets