IGFBP5 promotes diabetic kidney disease progression by enhancing PFKFB3-mediated endothelial glycolysis

Area of Science:

• Nephrology
• Metabolic Diseases
• Molecular Biology

Background:

• Renal inflammation is a key feature of diabetic kidney disease (DKD).
• The precise mechanisms driving inflammation in DKD are complex and effective clinical treatments are limited.
• Insulin-like growth factor-binding protein 5 (IGFBP5) is implicated in inflammation and fibrosis and is upregulated in DKD.

Purpose of the Study:

• To elucidate the role and underlying mechanisms of IGFBP5 in the renal inflammation associated with DKD.
• To investigate whether IGFBP5 contributes to kidney inflammation in a diabetic mouse model.

Main Methods:

• Assessed IGFBP5 levels in the kidneys of diabetic mice.
• Examined the effects of IGFBP5 ablation on kidney inflammation in DKD mice.
• Investigated the molecular mechanisms by which IGFBP5 influences glycolysis, including the role of early growth response 1 (EGR1) and PFKFB3 in endothelial cells.
• Utilized a PFKFB3 mutation model to assess its impact on renal inflammation in DKD.

Main Results:

• IGFBP5 levels were significantly elevated in the kidneys of diabetic mice.
• Ablation of IGFBP5 reduced kidney inflammation in DKD mice.
• IGFBP5 promoted glycolysis by activating EGR1 and increasing PFKFB3 expression in endothelial cells, leading to increased lactic acid and extracellular acidification.
• A mutation in PFKFB3 attenuated renal inflammation in DKD mice.

Conclusions:

• IGFBP5 exacerbates kidney inflammation in DKD by reprogramming the metabolism of glomerular endothelial cells.
• Targeting IGFBP5 or its associated metabolic pathways presents a potential therapeutic strategy for managing DKD.