Work

Dimethyl fumarate mitigates kidney injury induced by high-fat and high-cholesterol diet through reduction of oxidative stress and mitochondrial dysfunction

Year: 2025

Type: article

Abstract: Obesity is a major risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD), largely mediated by renal lipotoxicity, oxidative stress, and mitochondrial dysfunction. Dimethyl fumarate (DMF), a fumaric acid derivative with known antioxidant properties, has been extensively studied for its role in modulating oxidative stress; however, its protective effects and underlying mechanisms in obesity-induced kidney injury remain poorly understood. This study aimed to investigate the renoprotective effects and potential mechanisms of DMF in a high-fat, high-cholesterol (HFHC) diet-induced kidney injury model and palmitic acid (PA)-stimulated renal tubular epithelial cells. Our results demonstrated that DMF treatment significantly alleviated renal injury, fibrosis, and glomerular filtration barrier disruption by restoring lipid homeostasis in HFHC-fed mice. Mechanistically, DMF activated the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, which suppressed reactive oxygen species (ROS) accumulation and reduced nutrient overload-induced oxidative stress. NRF2 activation further upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. This promoted mitochondrial DNA transcription and replication. This coordinated NRF2-PGC-1α response contributed to improved mitochondrial structure and function, reduced mitochondrial fission, enhanced mitochondrial fusion, and suppressed apoptosis-related signaling, including cytochrome c (Cyt c) release and PUMA-caspase-3 activation, ultimately attenuating kidney injury. Collectively, these findings suggest that DMF may confer renoprotective effects by mitigating oxidative stress and preserving mitochondrial homeostasis, underscoring its potential as a therapeutic candidate for nutrient overload-associated kidney disease.

Source: Biochemical Pharmacology

DOI: 10.1016/j.bcp.2025.117278