Regulation of PKM2 expression and function by GLIS3 during metabolic reprogramming in polycystic kidneys

Area of Science:

• Molecular Biology
• Genetics
• Metabolic Diseases

Background:

• GLI-similar 3 (GLIS3) deficiency is linked to polycystic kidney disease (PKD).
• Glis3-knockout (KO) kidneys exhibit metabolic reprogramming, favoring aerobic glycolysis.
• The precise mechanism of GLIS3's role in regulating glycolysis remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which GLIS3 controls glycolytic gene expression.
• To investigate the role of GLIS3 in regulating pyruvate kinase M2 (PKM2) function in kidney cystogenesis.

Main Methods:

• Transcriptomic and cistromic analyses of Glis3-KO and wild-type kidneys.
• Chromatin immunoprecipitation sequencing to identify GLIS3-bound genomic regions.
• Analysis of PKM2 expression, phosphorylation, and activity in Glis3-KO models.
• siRNA-mediated knockdown and pharmacological inhibition of PKM2.

Main Results:

• Glis3-KO kidneys show upregulated glycolytic genes and downregulated gluconeogenic genes.
• GLIS3 directly regulates glycolytic genes, including Pkm, in coordination with HNF-1B.
• PKM2 expression, dimer formation, and phosphorylation are increased in Glis3-KO kidneys, promoting aerobic glycolysis.
• PKM2 knockdown and pharmacological inhibition significantly reduced spheroid growth and cystogenesis in GLIS3-deficient models.

Conclusions:

• GLIS3 is a novel regulator of glycolysis and PKM2 function.
• Dysregulation of GLIS3 and subsequent PKM2 hyperactivity contribute to metabolic reprogramming and cystogenesis in PKD.
• Targeting PKM2 represents a potential therapeutic strategy for GLIS3-deficiency-related PKD.