Pharmacological activation of aldehyde dehydrogenase 2 inhibits ferroptosis via SLC7A11/GPX4 axis to reduce kidney stone formation

Abstract

Abstract Calcium oxalate (CaOx) kidney stones pose a global health challenge due to their high prevalence and recurrence rates. While cell death mechanisms such as ferroptosis are known to play a crucial role in stone formation, the precise underlying mechanisms remain enigmatic. Aldehyde dehydrogenase 2 (ALDH2) is a metabolic enzyme of the ferroptosis product 4-hydroxy-2-nonenal (4-HNE). However, the function of ALDH2 in kidney stones is poorly understood. In this study, ALDH2 expression was assessed in kidney tissues and HK-2 cells using immunohistochemistry and western blot. Renal histology and crystal deposition were visualized through hematoxylin-eosin and Von Kossa staining. The expression of crystal-related molecules and ferroptosis-associated molecules was quantified via qPCR, western blot and immunohistochemical staining. Commercial assay kits were utilized to quantify glutathione, lipid peroxidation and Fe2+, and the activity of glutathione peroxidase 4 (GPX4). Rescue experiments involving siRNA targeting Solute Carrier Family 7 Member 11 (SLC7A11) were conducted to explore functional implications. Our data showed significant reduction of ALDH2 in the stone group. Alda-1, an agonist of ALDH2, notably mitigated crystal deposition in the kidneys and hindered crystal adhesion to cells. Furthermore, Alda-1 induced an upregulation of SLC7A11 expression, stimulating glutathione synthesis, reducing lipid peroxidation accumulation, and lowering Fe2+ levels, collectively contributing to the attenuation of ferroptosis triggered by crystal stimulation. Notably, SLC7A11 siRNA experiments confirmed the role of SLC7A11 in Alda-1-mediated renoprotection. In conclusion, our study highlights the potential of targeting ALDH2 as a promising therapeutical strategy for urolithiasis.