Free Nε-(carboxymethyl)-lysine promotes diabetic kidney disease progression via RAGE/NF-κB/NLRP3 pathway-mediated...

Area of Science:

• Nephrology
• Immunology
• Biochemistry

Background:

• Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease.
• PANoptosis, a novel inflammatory cell death, is implicated in DKD pathogenesis.
• Elevated serum Nε-(carboxymethyl)-lysine (CML), an advanced glycation end product, was previously observed in renal dysfunction.

Purpose of the Study:

• To investigate the diagnostic value and mechanistic role of free CML in DKD.
• To explore the involvement of PANoptosis in CML-induced kidney injury.
• To elucidate the molecular pathway linking CML to podocyte injury and DKD progression.

Main Methods:

• Serum CML levels were measured in DKD patients and controls.
• In vitro studies involved stimulating podocytes (MPC5 cells) with free CML.
• In vivo studies utilized CML injection in db/m and db/db mouse models.
• NF-κB and NLRP3 pathways were inhibited using specific agents and knockdown techniques.
• RAGE antagonism was assessed using FPS-ZM1.
• Molecular docking was employed to confirm interactions.

Main Results:

• Serum free CML levels were significantly elevated in DKD patients, suggesting diagnostic potential.
• Free CML induced oxidative stress, cell injury, and apoptosis in podocytes.
• In vivo CML administration exacerbated renal dysfunction and podocyte injury in mice.
• CML promoted PANoptosis via the RAGE/ROS/NF-κB/NLRP3 axis, leading to podocyte injury.
• Inhibitors of NF-κB, NLRP3, and RAGE attenuated CML-induced podocyte damage and slowed DKD progression.

Conclusions:

• Free CML is a potential biomarker for early DKD diagnosis.
• Free CML drives DKD progression by inducing podocyte PANoptosis through the RAGE/NF-κB/NLRP3 signaling pathway.
• Targeting the RAGE/NF-κB/NLRP3 axis offers a promising therapeutic strategy for managing DKD.