The AMPK/NRF2/FOXO Axis in CKD-Molecular and Clinical Perspectives

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Chronic Kidney Disease (CKD) is a major global health concern, projected to be the fifth leading cause of death by 2040.
• CKD progression is characterized by a cycle of mitochondrial dysfunction, oxidative stress, and inflammation.
• The AMPK-NRF2-FOXO axis, a critical regulator of renal homeostasis, is frequently impaired in CKD.

Purpose of the Study:

• To elucidate the molecular crosstalk within the AMPK-NRF2-FOXO axis in the context of CKD.
• To evaluate the therapeutic potential and limitations of modulating this axis with nutraceuticals and pharmacological agents.
• To contextualize the axis within current clinical management strategies for CKD based on KDIGO guidelines.

Main Methods:

• Review of molecular mechanisms governing the AMPK-NRF2-FOXO axis.
• Analysis of functional paradoxes within the axis.
• Evaluation of existing literature on therapeutic interventions targeting the axis.
• Examination of the axis in relation to the 2024/2026 KDIGO guidelines.

Main Results:

• AMPK acts as a sensor for metabolic and redox states, NRF2 mediates cytoprotective responses, and FOXO isoforms regulate autophagy, antioxidant defense, and senescence.
• Functional paradoxes exist within the axis, necessitating context-dependent therapeutic modulation.
• Nutraceuticals and agents like bardoxolone methyl show potential but require careful consideration of benefits and drawbacks.

Conclusions:

• The AMPK-NRF2-FOXO axis is a key player in CKD pathogenesis and a potential therapeutic target.
• Context-dependent modulation of the axis is crucial for effective treatment.
• Current KDIGO guidelines advocate a multi-targeted approach, incorporating agents like metformin, SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, and HIF-PH inhibitors, reflecting a shift in CKD management.