Nephroprotective Effects of Vanillic Acid on Bortezomib‐Induced Renal Injury: Role of Oxidative Stress, Mitochondrial Dysfunction, Apoptosis and miR‐204/Nephrin/Podocin/CD2AP Axis

Bortezomib (BTZ) is clinically important in the nephrological field because of its increasing use in plasma cell disorders and antibody-mediated kidney diseases, where it can both exert therapeutic benefits and, paradoxically, cause significant renal toxicity. This study investigated the protective effects of vanillic acid (VA) against BTZ-induced acute kidney injury using biochemical and molecular approaches. BTZ administration elevated serum creatinine, blood urea nitrogen, KIM-1 and NGAL, while co-treatment with VA partially normalized these markers. BTZ increased apoptotic markers (BAX, PUMA and TRAIL) and inflammatory cytokines (IL-1β, IL-6, TNF-α and IL-10), which were attenuated by VA. Oxidative stress-related genes NQO1, NOX4 and XO were upregulated, and GPX4 was downregulated by BTZ; VA restored these expressions. BTZ disrupted mitochondrial dynamics and energy metabolism (MFN2, CPT1A and OxPhos decreased; FIS1 increased), with VA ameliorating these changes. Energy imbalance induced by BTZ, reflected by reduced ATP and increased LDH and TAG, was also mitigated by VA. Podocyte proteins nephrin, podocin and CD2AP were reduced, accompanied by increased LAMP1 and decreased miR-204-5p; VA partially restored these levels. Overall, VA protected against BTZ-induced kidney injury via antioxidant, anti-inflammatory, antiapoptotic and mitochondrial mechanisms, potentially involving the miR-204-5p-nephrin axis.