Proanthocyanidin alleviates vancomycin-induced kidney injury via modulation of Nrf2/Keap1/HO1, Bax/Bcl-2/Caspase-3, and TLR4/MyD88/NF-κB pathways

Vancomycin (VAN), a complex tricyclic glycopeptide antibiotic, is currently utilized primarily in the therapy of bacterial infections for drug resistant Gram-positive bacteria. However, its clinical usage is restricted due to its association with renal toxicity at high doses. The potential efficacy of proanthocyanidin (PRO) on vancomycin-associated nephrotoxicity remains unclear. This current research aimed to assess the potential protective impacts of proanthocyanidin against vancomycin-associated nephrotoxicity and to assess the underlying mechanism. Wistar albino rats were split into 4 groups (8 rats per group) at random: Control (C), PRO (200 mg/kg/po), VAN (200 mg/kg, i.p., twice a day), and VAN+PRO (200 mg/kg, i.p., twice a day VAN, 200 mg/kg/po PRO). All administrations were applied for 7 days. PRO treatment alleviated VAN-induced oxidative stress by increasing antioxidants (SOD, CAT, GPx) and reducing elevated MDA levels, a marker of lipid peroxidation. PRO elevated antioxidant activity by triggering the Nrf2/Keap1/HO1 signaling pathway. VAN-induced elevations in proapoptotic p53, Bax, and caspase-3 levels were diminished by PRO, while the decrease in antiapoptotic Bcl-2 levels elevated, thereby alleviating apoptosis. Furthermore, VAN-induced increases in TLR4, MyD88, NF-κB, iNOS, IL-18, and TNF-α levels were reduced by PRO, while IL-10 levels increased, reducing the inflammatory response. PRO treatment caused an upregulation of PPARγ levels and a downregulation of GRP78 levels. Furthermore, PRO treatment preserved kidney function and structural integrity. Considering all these findings, proanthocyanidin may be effective in reducing vancomycin-induced renal injury by diminishing oxidative stress, inflammation, apoptosis, and ER stress in vancomycin-induced renal damage and activating protective cellular mechanisms through Nrf2/HO1 and PPARγ, and therefore can be considered an effective treatment option.