Free Radic Biol Med. 2026 Jun 6:S0891-5849(26)00868-3. doi: 10.1016/j.freeradbiomed.2026.06.017. Online ahead of print.
ABSTRACT
Obesity is a major risk factor for chronic kidney disease (CKD), partly mediated by oxidative stress. The liver is the primary source of glutathione (GSH), a key antioxidant that maintains tissue redox balance. Cystathionine γ-lyase (CSE) regulates cysteine availability for GSH synthesis; however, whether disruption of CSE-dependent GSH metabolism contributes to kidney injury under high-fat diet (HFD)-induced metabolic stress remains unclear. To investigate the role of CSE in HFD-induced kidney injury, CSE-deficient (Cse-/-) and wild-type (Cse+/+) mice were fed a normal-fat diet (NFD) or HFD for 16 weeks. Glutathione metabolism, oxidative stress, tissue damage, and function in the liver and kidney were analyzed. HFD feeding markedly reduced total GSH (tGSH) levels in the liver, plasma, and kidney, with more severe reductions in Cse-/- mice, suggesting impaired antioxidant capacity. Concomitantly, HFD induced greater oxidative stress in Cse-/- mice than in Cse+/+ mice, as evidenced by greater increases in hydrogen peroxide levels, lipid peroxidation, and the oxidized GSH-to-tGSH ratio. In addition, HFD decreased creatinine clearance, increased urinary protein, reduced renal hydrogen sulfide (HS) levels, and increased collagen deposition, transforming growth factor-β1, collagen I, plasminogen activator inhibitor-1, mitochondrial fission 1, Bcl-2-associated X protein expression, and TUNEL staining, with more pronounced changes in the kidneys of Cse-/- mice than in those of Cse+/+ mice, indicating that CSE deficiency aggravates HFD-induced renal fibrosis and dysfunction. These findings suggest that CSE deficiency exacerbates HFD-induced kidney injury in association with disrupted CSE-cysteine-GSH status, enhanced oxidative stress, and fibrosis, suggesting that this pathway may be a potential therapeutic target for HFD-associated kidney injury.
PMID:42252063 | DOI:10.1016/j.freeradbiomed.2026.06.017