Abstract
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•Troxerutin attenuated renal immune cell infiltration and kidney function markers.•It inhibited HMGB1/RAGE/NF-κB pathway and its downstream COX-2 and TNF-α signals.•It activated the AMPK/mTOR-driven autophagy.•It lowered the apoptosis markers (caspase-3, Bax, and Bax/Bcl-2 ratio).•It curbed the oxidative stress markers and activated the Nrf2/HO-1 pathway.
Troxerutin, a bioflavonoid with marked immune-modulatory and antioxidant features, has been proven to ameliorate experimental cardiotoxicity, hepatotoxicity, and neurodegeneration. However, its impact on methotrexate (MTX)-induced nephrotoxicity has not been investigated. In the current work, we aimed to investigate the potential of troxerutin to combat MTX-triggered renal injury, exploring immune cell infiltration, inflammation, autophagy, and apoptosis, with emphasis on the HMGB1/RAGE/NF-κB, AMPK/mTOR, and Nrf2/HO-1 pathways.
Troxerutin (150 mg/kg/day) was administered by oral gavage and the renal tissues were examined with the aid of biochemical assays, ELISA, histology, and immunohistochemistry.
Troxerutin mitigated MTX-induced renal dysfunction by significantly lowering creatinine, BUN, and KIM-1 alongside immune-cell infiltration and histopathologic aberrations. These favorable effects were mediated by inhibition of HMGB1/RAGE/NF-κB cascade via downregulating the protein expression of HMGB1, RAGE, and nuclear NF-κBp65 alongside its downstream signals, including COX-2 and TNF-α. Moreover, troxerutin activated the autophagy flux as evidenced by upregulating renal Beclin 1, lowering p62 SQSTM1 accumulation, and activation of AMPK/mTOR pathway, seen by increasing p-AMPK/total AMPK and lowering p-mTOR/total mTOR signals. In tandem, troxerutin combated renal apoptotic changes as proven with lowering caspase-3 activity, Bax expression, and Bax/Bcl-2 ratio and upregulating the proliferation signal PCNA. Additionally, the oxidative insult was attenuated by troxerutin, as evidenced by lowering NOX-1 and lipid peroxides, replenishing GSH, GPx, and SOD antioxidants, and activating Nrf2/HO-1 pathway.
Troxerutin attenuated MTX-triggered renal injury via inhibition of inflammation and apoptosis alongside activation of autophagy. Thus, it may serve as an adjunct modality for the management of MTX-linked nephrotoxicity.