Supplementation of 18β-glycyrrhetinic acid attenuates D-galactose-induced oxidative stress and inflammatory responses in kidneys of weaned piglet

Oxidative stress is a common issue in intensive pig production, threatening kidney health and increasing susceptibility to oxidative damage. 18β-Glycyrrhetinic acid (GA), a pentacyclic triterpenoid derived from the Glycyrrhiza genus, exhibits potent antioxidant and anti-inflammatory properties. This study evaluates the potential of GA in mitigating D-galactose (D-gal)-induced renal oxidative injury and explores the underlying mechanisms. Renal oxidative stress was induced in piglets by administering 10 g/kg BW of D-gal for 28 d, followed by a 28-d diet supplemented with 100 mg/kg/d of GA (n = 8 per group) to assess its mitigating effects. The results demonstrated that GA supplementation significantly enhanced T-AOC (P < 0.05) levels in D-gal-induced piglet kidneys, reduced 8-OHdG levels, increased SOD activity, and upregulated antioxidant genes (CAT, SOD1, SOD3), while downregulating iNOS (All P < 0.05). GA also reversed the elevated levels of TGF-β (P < 0.05) induced by D-gal. Histopathological analysis revealed that GA restored renal structure, reduced inflammation, and alleviated fibrosis. Transcriptomic analysis revealed that GA upregulated antioxidant genes such as SOD3 and GSTA1, while downregulating genes related to inflammation and fibrosis in D-gal-treated piglets. Moreover, GA inhibited the excessive extracellular matrix (ECM)-receptor interactions, PI3K-Akt signaling, and MAPK signaling pathways. Western blot analysis confirmed that GA supplementation significantly reduced PI3K levels (P < 0.05), tended to inhibit Akt phosphorylation (P = 0.099), and attenuated p38 MAPK phosphorylation (P < 0.05). GA also tended to increase Nrf2 expression (P = 0.071) and significantly upregulated HO-1 and NQO-1 protein levels (P < 0.05). These findings indicate that GA protects against D-gal-induced renal oxidative damage by activating the Nrf2 signaling pathway, while simultaneously alleviating fibrosis and inflammation through modulation of the TGF-β/PI3K/AKT and p38 MAPK pathways.