p21-Activated Kinase 4 and Ischemic Acute Kidney Injury in Mice and Humans

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Ischemia-reperfusion (I/R) induced acute kidney injury (AKI) presents a significant clinical challenge with limited therapeutic options.
• The role of p21-activated kinase 4 (PAK4) in renal I/R injury is currently unknown, despite its established involvement in hepatic I/R injury.

Purpose of the Study:

• To investigate the role of PAK4 in renal ischemia-reperfusion injury.
• To explore the therapeutic potential of targeting PAK4 in ameliorating AKI.

Main Methods:

• Utilized wild-type and proximal tubule–specific Pak4 knockout mice subjected to renal I/R injury.
• Employed in vitro models using primary tubular and human kidney-2 cells exposed to hypoxia-reoxygenation.
• Investigated the effect of a proteolysis-targeting chimera (PROTAC) designed for selective PAK4 degradation.

Main Results:

• PAK4 expression was upregulated in mouse kidneys post-I/R via hypoxia-inducible factor 1 α.
• Pak4 deletion in proximal tubules attenuated I/R-induced AKI, reducing markers of kidney damage, inflammation, and lipid accumulation.
• PAK4 mediated the phosphorylation and proteasomal degradation of GSH peroxidase 3 (GPx3), impairing antioxidant defense and fatty acid oxidation.
• PAK4 PROTAC treatment preserved GPx3 levels, enhanced fatty acid β-oxidation, and protected against AKI.
• Elevated PAK4 and phosphorylated GPx3 were observed in human kidney transplant tissues.

Conclusions:

• Renal tubular PAK4 plays a critical role in mediating tissue damage during I/R injury.
• PAK4 PROTAC therapy offers a promising strategy to mitigate AKI by reducing oxidative stress and promoting fatty acid metabolism.