HNF4A Regulated APEH Deficiency Promotes UPR Activation in Diabetic Kidney Disease

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Diabetic kidney disease (DKD) is a major cause of end-stage renal disease, driven by complications like endoplasmic reticulum stress (ERS).
• ERS, initiated by protein carbonylation from reactive oxygen species (ROS), activates the unfolded protein response (UPR) and promotes cell apoptosis.
• Acyl peptide enzyme hydrolase (APEH) degrades carbonylated proteins, but its role in DKD is unclear.

Purpose of the Study:

• To investigate the role and regulatory mechanisms of APEH in diabetic kidney disease (DKD).
• To elucidate the functional link between APEH, hepatocyte nuclear factor 4 alpha (HNF4A), protein carbonylation, and UPR signaling in DKD.

Main Methods:

• Utilized 24-week db/db mice and high glucose/high fat-stimulated renal tubular epithelial cells.
• Employed multidatabase bioinformatics, morphological analysis, and molecular biology techniques.
• Conducted dual-luciferase reporter assays and ChIP-qPCR to confirm gene regulation.

Main Results:

• DKD models showed reduced APEH and HNF4A expression, increased protein carbonylation, and activated UPR signaling.
• HNF4A was confirmed to directly regulate APEH expression via promoter binding.
• Impaired APEH function exacerbated protein carbonylation, UPR activation, and renal tubular cell apoptosis in DKD.

Conclusions:

• The HNF4A/APEH axis plays a critical role in regulating protein carbonylation and UPR signaling in DKD.
• Reduced APEH expression contributes to DKD progression by impairing protective mechanisms against oxidative stress and apoptosis.
• Targeting the HNF4A/APEH pathway presents a potential therapeutic strategy for diabetic kidney disease.