Background: Doxorubicin (DOX) is a widely used anticancer drug; However, its nephrotoxicity limits its therapeutic efficacy. This study investigates the protective effects of Perilla Alcohol (PA) against DOX-induced nephrotic syndrome (NS), focusing on its antioxidant and anti-inflammatory properties through the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways.

Methods: A DOX-induced nephrotic syndrome (NS) rat model and a DOX-treated Mouse Podocyte Cell line 5 (MPC5) cell model were used to evaluate the renal protective effects of PA. The rat model was divided into control, DOX, DOX + Prednisone, DOX + PA (50 mg/kg) and DOX + PA (100 mg/kg) groups. The effects of PA were assessed by measuring urinary protein excretion, blood biochemical markers, serum urea nitrogen, creatinine levels, cell viability, mitochondrial function and oxidative stress status. Additionally, Western blot and immunofluorescence staining were used to examine Nrf2 nuclear translocation, NF-κB signalling pathway, and intracellular antioxidant protein expression.

Results: Compared to the DOX group, rats in the DOX + PA groups showed significant reductions in 24-hour urinary protein and improvements in blood biochemical parameters (p < 0.01), indicating that PA enhanced renal function. At the cellular level, PA mitigated DOX-induced damage in MPC5 cells (p < 0.05, p < 0.01, and p < 0.001). Moreover, PA alleviated podocyte injury caused by DOX, reduced intracellular reactive oxygen species levels and improved mitochondrial membrane potential (p < 0.05, p < 0.01, and p < 0.001). Mechanistic studies revealed that PA protects against DOX-induced renal injury by inhibiting the NF-κB signalling pathway and restoring podocyte protein expression, while also alleviating oxidative stress through the activation of the Nrf2/antioxidant response element (ARE) pathway, contributing collectively to its protective effects (p < 0.05, p < 0.01, and p < 0.001).

Conclusions: PA ameliorates DOX-induced NS by modulating the NF-κB and Nrf2/ARE pathways, reducing oxidative stress. These findings provide a theoretical and experimental basis for the potential use of PA in preventing and treating DOX-induced renal injury, with implications for drug development and clinical applications.

Keywords: Nrf2; Perilla Alcohol; doxorubicin-induced nephrotic syndrome; kidney injury; oxidative stress.

© 2024 The Author(s).