The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family...

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Persistently elevated glycolysis contributes to chronic kidney disease (CKD) pathogenesis.
• The precise molecular mechanisms linking kidney glycolysis to CKD progression are not fully understood.

Purpose of the Study:

• To investigate the role of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in kidney proximal tubular cells (PTCs) during kidney injury and CKD.
• To elucidate the mechanism by which PFKFB3 influences kidney inflammation, fibrosis, and function.

Main Methods:

• Analysis of PFKFB3 expression in mouse kidney ischemia-reperfusion injury (IRI) models and human CKD patient samples.
• PTC-specific PFKFB3 deletion in mice and treatment with a PFKFB3 inhibitor.
• Assessment of kidney lactate levels, inflammation, fibrosis, and function.
• Investigation of histone lactylation (H4K12la) and NF-κB signaling pathway activation.

Main Results:

• PFKFB3 was significantly upregulated in PTCs following IRI and in human CKD kidneys, correlating with fibrosis severity.
• PTC-specific PFKFB3 deletion or inhibition reduced kidney lactate, inflammation, and fibrosis, preserving kidney function.
• PFKFB3-derived lactate promoted H4K12la, which activated NF-κB signaling genes, thereby enhancing inflammation.

Conclusions:

• Tubular PFKFB3 promotes kidney fibrosis and inflammation in CKD through lactate production and NF-κB pathway activation.
• Targeting the PFKFB3-NF-κB axis in kidney tubular cells represents a potential therapeutic strategy for CKD.