Theabrownins improve burn-induced kidney injury by increasing the levels of guanidinoacetic acid and fumaric acid

Background: Burns are a common and serious health issue, with severe burn-induced acute kidney injury (AKI) being a major factor contributing to poor recovery and increased mortality in patients. Theabrownins (TBs), bioactive compounds formed during tea leaf fermentation, have shown promising effects on reducing inflammation, combating oxidative stress, and enhancing metabolic function. However, the roles and mechanisms of TBs in burn-induced kidney injury are still not fully understood.

Methods: The dorsal skin of 3-month-old mice was exposed to hot water for 10 s to induce burn-related renal injury. The mice were then orally administered TBs (40 mg/kg and 400 mg/kg). After 24 h of treatment, the mice were sacrificed for tissue collection. Transcriptomic and metabolomic analyses were performed to identify the pathways modulated by TBs. Metabolomics revealed TB-associated renal metabolites, such as guanidinoacetic acid (GAA) and fumaric acid (FA). Renal tubular epithelial (HK2) cells pretreated with GAA and FA were exposed to hydrogen peroxide (H₂O₂), cisplatin (CDDP) and erastin to establish a cell injury model. Changes in the levels of relevant molecules were assessed using quantitative RT-PCR, Western blotting, and fluorescence staining.

Results: TB treatment significantly increased the survival rate and reduced kidney injury in mice with burn injury. Multiomics analyses and molecular experimental validation revealed that TB treatment downregulated the inflammation, Apoptosis, and Ferroptosis pathways in the kidneys of mice with burn injury and increased the levels of the renal metabolites GAA and FA. Cellular experiments confirmed that GAA and FA alleviated H₂O₂-, CDDP- and erastin-induced renal tubular epithelial cell injury by inhibiting Apoptosis and Ferroptosis.

Conclusions: Burns induce inflammation and kidney damage by upregulating the Apoptosis and Ferroptosis pathways in renal tissue. TBs alleviate burn-induced renal Apoptosis and Ferroptosis by increasing the levels of GAA and FA in the kidneys, thereby ameliorating kidney damage. This study innovatively and systematically evaluated the ability of TBs to ameliorate burn-induced kidney injury and, for the first time, identified the potential mechanism by which TBs ameliorate burn-induced kidney damage by increasing the levels of the metabolites GAA and FA in the kidneys.

Acute kidney injury; Burn; Fumaric acid; Guanidinoacetic acid; Theabrownins.