Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy

Area of Science:

• Nephrology
• Metabolic pathways
• Genetic disorders

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic kidney disorder causing bilateral renal cysts.
• Despite ongoing clinical trials targeting signaling pathways, effective therapies for ADPKD remain elusive.
• A metabolomic approach is employed to uncover novel therapeutic targets.

Purpose of the Study:

• To identify and characterize a pathogenic metabolic pathway in ADPKD.
• To investigate the role of glycolysis in ADPKD progression.
• To evaluate the therapeutic potential of targeting glucose metabolism.

Main Methods:

• Metabolomic analysis of PKD1-mutant cells and ADPKD patient kidneys.
• Assessment of cell proliferation and apoptosis under glucose deprivation.
• Treatment of two distinct PKD mouse models with 2-deoxyglucose (2DG).
• Investigation of the extracellular signal-related kinase (ERK) and AMP-activated protein kinase (AMPK) pathways.

Main Results:

• PKD1 mutation leads to enhanced glycolysis in ADPKD models and human kidneys.
• Glucose deprivation increases apoptosis and reduces proliferation in PKD1-mutant cells.
• 2DG treatment significantly reduced kidney weight, volume, cystic index, and proliferation in PKD mouse models.
• Metabolic alterations involve the ERK pathway, impacting the LKB1-AMPK axis and mTORC1-glycolytic cascade.

Conclusions:

• Defective glucose metabolism is a key factor in ADPKD pathobiology.
• Targeting glycolysis presents a promising therapeutic strategy for ADPKD.
• Existing drugs, like 2DG, could be repurposed for ADPKD treatment, individually or in combination.