Aldehyde dehydrogenase 2 mitigates acrolein-driven ferroptosis to preserve kidney function

Area of Science:

• Nephrology
• Toxicology
• Biochemistry

Background:

• Acrolein is a reactive aldehyde causing oxidative renal injury.
• Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehydes, but the ALDH2*2 variant impairs this function.
• This impairment may increase susceptibility to acrolein-induced kidney damage.

Purpose of the Study:

• To investigate the mechanism of acrolein nephrotoxicity.
• To evaluate the role of ferroptosis and mitochondrial dysfunction.
• To assess the therapeutic potential of ALDH2 activation in acrolein-induced kidney injury.

Main Methods:

• Primary mouse proximal tubular epithelial cells (PTECs) were used to study acrolein toxicity.
• Aldh2*2 cells were compared to wild-type cells.
• Pharmacological inhibitors and ALDH2 activators were employed.
• In vivo studies used Aldh2*2 mutant mice treated with AD-9308.

Main Results:

• Acrolein induced ferroptosis and mitochondrial dysfunction in PTECs.
• Aldh2*2 cells exhibited greater cytotoxicity and acrolein-induced damage.
• ALDH2 activators restored enzyme activity, reduced oxidative stress, and improved cell viability.
• AD-9308 treatment protected Aldh2*2 mice from acrolein-induced kidney injury.

Conclusions:

• Ferroptosis is a key mechanism in acrolein nephrotoxicity.
• ALDH2 activation is a promising therapeutic strategy for acrolein-induced kidney injury.
• This approach is particularly relevant for individuals with the ALDH2*2 variant.