Hesperidin and Its Polylactic- <i>co</i> -glycolic Acid-Nanoformulation Mitigate Rhabdomyolysis-Induced Acute Kidney Injury via Attenuation of Oxidative Stress and Inflammation in BALB/c Mice

<i>Background & Aim</i>: Preservation of renal morphology and function is essential in rhabdomyolysis (RM)-induced acute kidney injury (RIAKI) for which there is no established treatment. Hesperidin (HSP), a natural bioflavonoid with antioxidant and anti-inflammatory potential, seems promising for RIAKI prevention. Here, we evaluated the nephroprotective potential of HSP and compared it with its polylactic-<i>co</i>-glycolic acid (HSP-PLGA) nanoformulation in RM. <i>Methodology</i>: HSP-PLGA was developed by nanoprecipitation and validated by zeta potential, scanning electron microscopy, and Fourier-transform infrared analysis. BALB-c mice were pretreated with intraperitoneal HSP and HSP-PLGA. RM was induced using intramuscular glycerol. Serum lactate dehydrogenase (LDH), creatine kinase (CK), creatinine, and urea were estimated. H&E, PAS, and immunohistochemistry for hemoxygenase-1, tumor necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were done. Tissue levels of lipid peroxidation (LP), superoxide dismutase (SOD), reduced glutathione (GSH), and nitric oxide (NO) were determined. ELISA was used to estimate interleukin-6 (IL-6), interleukin-10 (IL-10), and interferon-γ levels. <i>Results</i>: A significant increase in serum CK, LDH, urea, and creatinine validated the RIAKI model. Treatment with HSP and HSP-PLGA significantly reduced serum urea and creatinine levels. Intervention also enhanced antioxidant defense by lowering LP and NO, and increasing SOD and GSH levels. HSP and HSP-PLGA reduced inflammation by suppressing TNF-α, iNOS, IL-6, and interferon-γ, and increasing IL-10. Histologically, this translated into reduced hyaline casts and tubular necrosis. These promising findings were validated by increased expression of the protective enzyme hemeoxygenase-1, thus highlighting the compound's potential in mitigating RIAKI. Moreover, nanoeffect calculation on different parameters exhibited more pronounced effects of HSP-PLGA over HSP. <i>Conclusion</i>: HSP decreases oxidative stress and inflammation, thus preserving renal morphology and function. HSP-PLGA enhances the nephroprotective effects of HSP.