Ferulic acid-mediated selenium nanoparticles attenuate oxaliplatin-induced renal injury in type 2 diabetic rats via modulation of oxidative stress, SIRT1/HMGB1/TLR4 signaling, endoplasmic reticulum stress, and apoptosis.

Background

Patients with type 2 diabetes mellitus (T2DM) are susceptible to chemotherapy-induced renal injury because of pre-existing oxidative stress, inflammation, and impaired antioxidant defenses. Ferulic acid-mediated selenium nanoparticles (FA-SeNPs) combine the antioxidant properties of ferulic acid with the biological advantages of selenium nanoparticles and may provide superior renoprotection against oxaliplatin-induced nephrotoxicity.

Methods

FA-SeNPs were synthesized using a green reduction approach and characterized by dynamic light scattering, zeta potential analysis, FT-IR spectroscopy, and TEM. Forty-two adult male Wistar rats were allocated into six groups (n = 7/group): control, T2DM, T2DM + oxaliplatin (OXL), T2DM + OXL + ferulic acid, T2DM + OXL + sodium selenite, and T2DM + OXL + FA-SeNPs. Renal function biomarkers (urea, creatinine, cystatin C, KIM-1, and NGAL), oxidative stress indices, antioxidant defenses, inflammatory mediators, SIRT1/HMGB1/TLR4 signaling, apoptosis-related proteins, endoplasmic reticulum stress-associated genes (GRP78, PERK, IRE1, and ATF6), and renal histopathology were evaluated.

Results

Oxaliplatin markedly aggravated diabetes-associated renal dysfunction, oxidative damage, inflammation, endoplasmic reticulum stress, and apoptosis. FA-SeNP treatment significantly improved renal function by reducing serum urea, creatinine, cystatin C, KIM-1, and NGAL compared with untreated diabetic oxaliplatin-exposed rats. FA-SeNPs also markedly decreased renal lipid peroxidation while restoring GSH, SOD, CAT, GPx, and Nrf2/HO-1 signaling. Furthermore, treatment suppressed IL-6, NF-κB, COX-2, HMGB1, TLR4, Bax, caspase-3, and ER stress-related transcripts (GRP78, PERK, IRE1, and ATF6), increased IL-10, SIRT1, and Bcl-2, and consistently demonstrated greater renoprotective efficacy than free ferulic acid or sodium selenite across most evaluated parameters.

Conclusions

Ferulic acid-mediated selenium nanoparticles effectively protected against oxaliplatin-induced renal injury in T2DM rats via coordinated antioxidant, anti-inflammatory, anti-apoptotic, and endoplasmic reticulum stress-modulating mechanisms involving activation of the SIRT1/Nrf2/HO-1 axis and inhibition of HMGB1/TLR4 signaling. These results support FA-SeNPs as a promising multifunctional nanotherapeutic strategy for reducing chemotherapy-associated nephrotoxicity in diabetic patients and warrant further translational investigation.